Vol. 18, No. 22, June 30, 1989 NOTICES RELEASE OF INFORMATION ON INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS ............................................(84/98)................... 1 Division of Research Grants Index: DIVISION OF RESEARCH GRANTS REMINDER: REPRODUCIBILITY OF REFERENCE LETTERS ...(101/113)................. 1 Division of Research Grants Index: DIVISION OF RESEARCH GRANTS CONFERENCE GRANT RECEIPT DATES ....................(116/140)................. 1 National Cancer Institute Index: CANCER DATED ANNOUNCEMENTS (RFPs AND RFAs) ROLE OF PROTO-ONCOGENES IN MAMMALIAN DEVELOPMENT (RFA) ..(146/206)........... 1 National Institute of Child Health and Human Development (724/967) Index: CHILD HEALTH AND HUMAN DEVELOPMENT NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS): OPPORTUNISTIC INFECTIONS (RFA) ............................(209/316, 970/2086)............. 2 National Institute of Allergy and Infectious Diseases Index: ALLERGY AND INFECTIOUS DISEASES ALCOHOL RESEARCH CENTER GRANTS (RFA) ....................(321/381)........... 4 National Institute on Alcohol Abuse and Alcoholism Index: ALCOHOL ABUSE AND ALCOHOLISM ONGOING PROGRAM ANNOUNCEMENTS SPECIAL EMPHASIS RESEARCH CAREER AWARD (KO1) FOR SOCIAL AND BEHAVIORAL SCIENTISTS IN BEHAVIORAL GERIATICS RESEARCH ..(387/670)........... 4 National Institute on Aging Index: AGING NOTICES RELEASE OF INFORMATION ON INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS P.T. 22; K.W. 1014006 Division of Research Grants In the past, the information available to the public on Individual National Research Service Awards was limited to the field of training, the title of the project, the sponsoring institution and the name of the awardee. Now, the dollar amount may be disclosed for the Individual Fellowship (F32) awards. The disclosure of this dollar amount does not constitute an unauthorized disclosure from a Privacy Act system of records because this amount is not "information about an individual." The amount is a composite of three separate dollar amounts, and the Fellow's stipend amount is not discernible from this total figure. REMINDER: REPRODUCIBILITY OF REFERENCE LETTERS P.T. 22, 34; K.W. 1014006 Division of Research Grants When submitting reference letters with an application for a Fellowship, Research Career Development Award (RCDA), First Independent Research Support and Transition (FIRST) Award, Clinical Investigator Award, etc., remind your respondents to use a typewriter with a black ribbon or a pen with black ink. Please do not use blue ink or any color other than black. Blue ink does not reproduce well and causes delays in the processing and duplication of the application in preparation for review. CONFERENCE GRANT RECEIPT DATES P.T. 42; K.W. 1014006 National Cancer Institute Prospective applicants interested in seeking support of scientific meetings from the National Cancer Institute (NCI) are advised that beginning October 1, 1989, applications will be accepted on receipt dates (February 1, June 1, and October 1) published by the Division of Research Grants (DRG), National Institutes of Health (NIH), in the information and instructions for form PHS 398 (Revised 10/88) and booklet on "Support of Scientific Meetings", August 1988. Waiver of the receipt date for exceptional circumstances may be requested as instructed in the above referenced booklet which may be obtained from the Office of Grant Inquiries, DRG at the address below. Specific questions regarding the NCI conference grant program may be referred to the NCI Conference Grant Coordinator (Phone 301-496-7173). Office of Grant Inquiries Division of Research Grants Westwood Building, Room 449 Bethesda, Maryland 20892 Telephone: (301) 496-7441 DATED ANNOUNCEMENTS (RFPs AND RFAs) ROLE OF PROTO-ONCOGENES IN MAMMALIAN DEVELOPMENT RFA AVAILABLE: 89-HD-03 P.T. 34; K.W. 1002058, 0775000, 0413002 National Institute of Child Health and Human Development Application Receipt Date: October 11, 1989 The Genetics and Teratology Branch (GTB) of the Center for Research for Mothers and Children (CRMC) of the National Institute of Child Health and Human Development (NICHD) invites research grant applications for studies on Vol. 18, No. 22, June 30, 1989 - Page 1 the role of proto-oncogenes in mammalian development. This initiative has important implications for both basic science and clinical studies. The information expected from the investigation of the role of proto-oncogenes in mammalian development will further our understanding of the specific molecules that are important in that process. In addition, underlying principles that direct normal patterns of growth, differentiation and morphogenesis and against which aberrations of these processes can be understood will be further defined. In a clinical context, these studies provide the basis for an improved understanding of the possible causes of birth defects and other developmental abnormalities that lead to early embryonic wastage and spontaneous abortion. In this regard, understanding the role of proto-oncogenes in mammalian development, particularly during early postimplantation, will be especially valuable since it is thought that a large number of reproductive failures in humans occur shortly after implantation. The primary goal of this Request for Applications (RFA) is to support a group of projects that are devoted to the investigation of the role of proto-oncogenes during mammalian development. It is expected that the latest molecular genetics technologies will be employed, including the generation of appropriate reagents and the possible production of either chimeric or transgenic animals. Applications should be submitted on Form PHS 398 (rev. 10/88), available in business or grants offices at most academic research institutions or from the Division of Research Grants, NIH. The RFA label available in the 10/88 version of Form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. This program will be funded through the traditional individual research project award program of NICHD. Grant applications will be reviewed at a single competition by an initial review group convened by NICHD. It is anticipated that four (4) grants will be awarded under this program, contingent upon the receipt of a sufficient number of meritorious applications and the availability of funds. Requests for copies of the full RFA should be addressed to: Joel M. Schindler, Ph.D. Genetics and Teratology Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development Executive Plaza North, Room 643C Bethesda, Maryland 20892 Telephone: (301) 496-5541 NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS): OPPORTUNISTIC INFECTIONS RFA AVAILABLE: 89-AI-18 P.T. 34; K.W. 0715008, 0740020, 0755025, 0715125, 1002008, 1003006 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: August 1, 1989 Application Receipt Date: December 8, 1989 The National Institute of Allergy and Infectious Diseases (NIAID) announces the availability of a Request for Applications (RFA) for funding of the National Cooperative Drug Discovery Groups for the Treatment of Acquired Immune Deficiency Syndrome (AIDS): Opportunistic Infections (NCDDG-OI). It is the purpose of this RFA (available upon request) to invite applications aimed at the discovery of therapeutic agents to treat infections caused by opportunistic pathogens associated with AIDS. Applications which include research projects or core components from the private sector (e.g., pharmaceutical, chemical, or biotechnological companies) are encouraged. Opportunistic infections are the major causes of morbidity and mortality in AIDS patients. Due to the complexity of managing these infections, the medical and hospitalization costs of HIV-infected individuals are enormous. Available drugs to treat the opportunistic infections are of limited utility because of toxicity and other adverse reactions. Therefore, the need exists for potent and selective therapeutic agents active against the infections. The purpose of this RFA is to encourage investigators from diverse fields and expertise to collaborate and to explore new avenues utilizing the recent Vol. 18, No. 22, June 30, 1989 - Page 2 advances in molecular biology. Units in which these research talents and resources are combined are termed "NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS" (NCDDGs). The NCDDG programs would provide a mechanism for a formalized collaboration between scientists from universities, pharmaceutical companies and government. They are envisioned as having the capacity to generate new approaches and strategies for the treatment of opportunistic infections in AIDS patients and to rapidly translate their concepts into potentially effective treatment. The NCDDG can be focused in one area (synthetic, biochemical, biological) or be a combination of the above approaches (comprehensive) in composition. Results from the research proposed should be used to identify and develop information for long-term planning of potential therapeutic approaches or to recommend new potential treatments worthy of further development in clinical trials. The NCDDG-OI initiative has evolved as a part of the NCDDG Program on AIDS. The NCDDG-AIDS Program, launched in 1986, has funded 28 groups whose research efforts are directed towards the identification of more selective and effective agents to treat HIV infection. Investigators from 45 public institutions and 21 private companies are currently involved in this program. The studies supported by the NCDDG-AIDS Program have led to the identification of several potential new therapeutic agents. The NCDDG-OI initiative seeks to stimulate investigations leading to the identification and preclinical development of agents active against the various pathogens causing opportunistic infections in AIDS patients. Recent advances in molecular biology, biochemistry and pathogenesis provide avenues for innovative approaches. The NCDDG-OI Program will provide assistance to talented scientists to interact as a unit to carry out the preclinical research essential for the realization of project objectives. An NCDDG-OI could be composed of scientists from a combination of academic, non-profit research, and commercial organizations. Each NCDDG-OI will be assembled by the Principal Investigator to form a multidisciplinary consortium representing the various skills needed to successfully design, synthesize, and evaluate, at the preclinical level, potential therapeutic agents useful in the treatment of opportunistic infections in AIDS patients. Specifically excluded from the Group's activities are studies related to clinical evaluation of the drug. Awards will be made as Cooperative Agreements. The Cooperative Agreement funding mechanism differs from the traditional research grant in that the Government component (NIAID) awarding the Cooperative Agreement anticipates substantial involvement during performance. The nature of NIAID staff participation is described in the RFA. However, the Principal Investigator must define its objectives in accord with its own interests and perceptions of approaches to the treatment of AIDS-associated opportunistic infections. The applicant institution and the Principal Investigator will be responsible for the Group's application. Awards will be made to the applicant institution on behalf of the group as a whole and not to individual research projects with the Group. The applicant institution will provide a Central Operations Office for the Group. The applicant institution will be responsible for the performance of the entire Group and will be accountable for the funds awarded. The participation of the Government through the NIAID extramural staff is aimed at facilitating a concerted effort by the Group by making available to the Group biological materials for testing, appropriate existing data bases, ancillary testing and other resources available under existing contracts and to provide appropriate scientific input. The interaction of academic and non-profit research institutions with commercial organizations and Government is expected to favor efficient invention of agents active against OIs in AIDS patients and will facilitate their subsequent development for clinical trials. NIAID anticipates making multiple awards for project periods up to five years and has set aside $3.5 million total costs for the initial year's funding. The amount spent will be dependent on the continuing availability of funds for this purpose and the quality and diversity of approved applications. For a copy of the RFA, please contact: Ms. Nancy R. Brown Developmental Therapeutics Branch AIDS Program National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 243P Bethesda, Maryland 20892 Telephone: (301) 496-8199 Vol. 18, No. 22, June 30, 1989 - Page 3 ALCOHOL RESEARCH CENTER GRANTS RFA AVAILABLE: 89-AA-07 P.T. 04, AA; K.W. 0404003, 0404000, 0415001, 0745070 National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: December 1, 1989 Application Receipt Date: February 15, 1990 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is planning to hold another competition for Alcohol Research Center grants. Applications are solicited to establish a new Center on Treatment Research and for a Center on Adolescent Development and Behavioral Change. Applications submitted in response to this Request for Applications (RFA) will be evaluated with applications submitted by three currently funded Centers seeking renewal support. The number of new grants to be awarded, as well as the level of support, will be determined on a competitive basis by the application review process, program needs, and the availability of funds. RESEARCH OBJECTIVES AND MECHANISM OF SUPPORT The Alcohol Research Centers Program is designed to complement the regular research grant programs of NIAAA. The program provides long-term support (usually five years) for interdisciplinary research programs with a distinct focus on a particular research theme related to alcoholism and other problems associated with alcohol abuse. The program is intended to help attract the best scientists from biomedical, behavioral, and social science disciplines to work on research problems related to alcohol abuse and alcoholism, and to provide a stable environment for such persons to engage in alcoholism research in a coordinated and integrated fashion. A Center is expected to be a source of excellence in research and, through sustained excellence, become a significant regional or national research resource. In addition, Centers are expected to afford opportunities for training in alcohol research to persons from various disciplines and professions. REVIEW PROCEDURES Each Alcohol Research Center application will be reviewed by a group of experts to evaluate the scientific and technical merit of the proposal. Recommendations resulting from this review will be presented to the National Advisory Council on Alcohol Abuse and Alcoholism which will meet in September 1990 to make a final recommendation to the Director, NIAAA. Grant awards will be made with a start date of December 1, 1990, or later. METHOD OF APPLYING AND INQUIRIES Potential applicants are urged to request a copy of the RFA, which contains more information about application procedures, program requirements and review criteria, by writing to: Dr. Albert A. Pawlowski Associate Director N.I.A.A.A - Division of Basic Research Parklawn Building, Room 14C-20 5600 Fishers Lane Rockville, Maryland 20857 Telephone: (301) 443-1273 ONGOING PROGRAM ANNOUNCEMENTS SPECIAL EMPHASIS RESEARCH CAREER AWARD (KO1) FOR SOCIAL AND BEHAVIORAL SCIENTISTS IN BEHAVIORAL GERIATRICS RESEARCH P.T. 34; K.W. 0710010, 0404000, 0745027, 0745035, 0710030 National Institute on Aging The National Institute on Aging (NIA) solicits applications for SPECIAL EMPHASIS RESEARCH CAREER AWARDS (SERCA) from eligible institutions for interdisciplinary and research support and career development of qualified social and behavioral scientists seeking careers in behavioral geriatrics research.1/ Vol. 18, No. 22, June 30, 1989 - Page 4 I. BACKGROUND Behavioral geriatrics research is an emerging area of behavioral medicine.2/ It is undertaking the development and integration of social/behavioral and biomedical science knowledge relevant to health promotion and the prevention and treatment of disease in the middle and later years. Research in this area is concerned with a wide range of health-related behaviors and attitudes that are influenced by the environment and that interact with biological, psychological, and social aging processes to promote or inhibit health and effective functioning as people grow older. Not only are the health behaviors and attitudes of middle-aged and older people themselves involved, but also those of formal health-care providers and of family and friends. These behaviors and attitudes include medical beliefs about the nature of the aging processes. They also include behaviors believed by older people to promote health and functioning, as well as "illness behaviors" that involve how older individuals monitor their bodily functioning; how they define and interpret symptoms perceived as abnormal; whether they consult with non-professional relatives and friends; whether they take or fail to take remedial action, utilize formal health-care systems, or comply with prescribed regimens; and how they approach death. II. PURPOSE OF THE AWARD The NIA Special Emphasis Research Career Award (SERCA) in behavioral geriatrics research focuses on identifying common ground between psychosocial and biomedical approaches. The award offers an opportunity for established social and behavioral scientists to acquire supplementary biomedical research knowledge and interdisciplinary research experience in order to pursue or enhance an interdisciplinary research career in aging and the promotion of health. This SERCA is intended to foster the career development of researchers with interests in these and related topics by encouraging qualified individuals to acquire in-depth experience and skills in the basic and clinical scientific disciplines that bear upon this area. The award provides support for up to a five-year program of full-time research training and interdisciplinary research experience in a clinical or biomedical setting. The award aims at a close and extended working relationship between a social or behavioral scientist (the awardee) and one or more highly qualified biomedical or biobehavioral scientists. The relationship should optimize the opportunity for interdisciplinary communication and collaboration in research on aging and health. For the candidate, the relationship should develop the capacity to apply the knowledge and research methods of his/her discipline to issues in behavioral geriatrics research requiring complementary biological or medical understanding. For the sponsoring institution, the relationship should stimulate awareness among biomedical scientists of the potential for interdisciplinary or cross-disciplinary research in aging. III. PROVISIONS OF THE AWARD The NIA-SERCA award is made to eligible institutions for up to 5 years of support of a unique working relationship between awardee and institution involving full-time research and related activities as specified below. A. Plan of Work Developmental Phase: During the first year or two the awardee is expected to develop capabilities for conducting interdisciplinary behavioral geriatrics research on aging and health promotion. The awardee's activities may include participation in formal courses, ongoing research, workshops, symposia, scientific and professional meetings, as well as involvement in care of older patients to the extent that this will strengthen research skills. Included in the plan should be exposure to at least one biomedical specialty (excluding psychiatry), such as general or geriatric medicine, immunology, neurology, neuroendocrinology, pharmacology, nutrition, cardiology. Exposure to epidemiological methods or biostatistical skills is also desirable if lacking from candidate's current background. These activities should be oriented around an area of research in behavioral geriatrics in which, subsequent to the grant period, the awardee contemplates the future development of a research program. Project Phase: Beginning as early as possible, the awardee is expected to engage with his/her sponsor or another biomedical/biobehavioral collaborator in a research project. This project, which should be designed as a basis for more extended research, can take such forms as (but not limited to): an exploratory or feasibility study, a test of a new technique, or development of a new biobehavioral measure. Vol. 18, No. 22, June 30, 1989 - Page 5 The project, preferably interdisciplinary or cross-disciplinary, must focus on a topic with clear implications for the linkages between health-related attitudes or behaviors and health outcomes (or prevention of disease) in older people. B. Relationship to Institution Throughout the grant period, the sponsoring institution (which may be the applicant's own institution) is expected to arrange significant working relationships with the awardee through an advisor who will sponsor and oversee the proposed program, and who will make sure that the awardee will receive the proper experience for a future career of interdisciplinary research in behavioral geriatrics. The advisor must be a biomedical scientist or a social/behavioral scientist with extensive interdisciplinary research experience at the interface of biomedical and social/behavioral sciences. A background in aging, though desirable, is not essential, if the candidate already possesses such expertise. C. Duration This award is for continuous support of biomedical research training and interdisciplinary research over a period of up to five consecutive years. The award is non-renewable. However, development of a separate and subsequent application for research support (e.g., for expansion of the research project) would be desirable either towards the end or following the award. D. Allowable Award Costs The NIA-SERCA grant is made annually to the sponsoring institution for the purpose of supporting the awardee's biomedical research career development and the interdisciplinary research project. Costs allowed may include: Awardee's Salary Up to a maximum of $40,000 from SERCA funds for full-time salary support may be requested. In addition, fringe benefits will be provided on that part of the salary paid from SERCA. Institutional supplementation is permitted. One hundred percent effort on this award is expected with a minimum of 75 percent in the conduct of research. Research Support In addition to the awardee's salary, up to a maximum of $10,000 in each of the first three years and up to a maximum of $20,000 in each of the subsequent years may be requested for research expenses: e.g., instrument development, data collection, analysis costs, technical assistance, consultant costs, domestic travel, patient care expenses, publication costs, and other appropriate expenses which are essential to the proposed program. Tuition If essential to the awardee's individual development program, funds for tuition for training courses may be requested. Sponsor Up to five percent of the primary advisor's salary will be allowed for the first two years. IV. CRITERIA FOR ELIGIBILITY A. The Candidate 1. The candidate must hold a Ph.D. or equivalent professional degree in a social or behavioral science (e.g., psychology, sociology, anthropology) and show evidence of expertise in his/her home discipline (e.g., by scholarly publications). 2. By the beginning date of the award, the candidate must have a minimum of three years post-doctoral research experience. This experience should include evidence of (a) clear intention to pursue research on aging and (b) interest in a scientific area that can be furthered through exposure to complementary biomedical approaches. In addition to bringing in people new to interdisciplinary behavioral geriatrics research, the goal of the award is to Vol. 18, No. 22, June 30, 1989 - Page 6 enhance the career development of social and behavioral scientists already involved in interdisciplinary health and behavior research. 3. The candidate already agrees to inform the NIA for a period of five years subsequent to completion of the award about his/her research activities, publications, grants or contracts, and academic status; and must agree to attend any scheduled meetings of awardees at NIA. 4. The candidate must be a citizen or noncitizen national of the United States or its possessions and territories or must have been lawfully admitted to the United States for permanent residence at the time of application. 5. Applications from woman and minority candidates are especially solicited. B. The Program of Activity 1. The candidate's program of activity must be fully described in terms of adequately providing biomedical training and interdisciplinary experience relevant to research in behavioral geriatrics. 2. For the research project, the general area must be defined and the research plan described in the grant application, (e.g., identification and justification of the interdisciplinary research problem; indication of possible study population(s), hypotheses, and variables; and strategies for analysis.) It is anticipated that full details will be formulated during the first two years of the grant period. C. The Sponsoring Institution 1. The sponsoring institution must nominate the candidate on the basis of qualifications, interests, accomplishments, motivation, and potential for an interdisciplinary research career in behavioral geriatrics. 2. Evidence of the commitment of the institution to the candidate's research development must be provided. 3. The background, qualifications, and commitment of the major biomedical advisor must be described. V. APPLICATION AND REVIEW PROCEDURES Applications should be submitted on Form PHS 398 (rev. 10/88), available at most institutional business offices or from the Division of Research Grants (DRG) NIH. A. Staff Contact and Supplementary Guidelines Prospective applicants need to obtain the complete version of this announcement, as well as Supplementary Guidelines, and to discuss their eligibility and proposed activities by contacting: Behavioral Geriatrics Research (SERCA) Behavioral & Social Research Program National Institute on Aging Building 31, Room 5C32 Bethesda, Maryland 20892-4500 Telephone: (301) 496-3136 B. Submission of Application Follow the "Supplementary Guidelines for Preparing Application, NIA-SERCA." Mail the completed application and six copies to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, Maryland 20892** C. Application Receipt and Review Schedule NIA-SERCA applications will be received three times per year according to the following schedule: APPLICATION RECEIPT COUNCIL REVIEW START DATE February 1 Sep/Oct December 1 June 1 Jan/Feb* April 1* October 1 May* July* *of the year following application receipt Vol. 18, No. 22, June 30, 1989 - Page 7 Amended applications also must be submitted for the same receipt dates. D. Review of Applications Review of the applications for scientific and technical merit will be conducted by the Gerontology/Geriatrics Review Committee, NIA. In this review, particular attention will be given to the candidate's prior training, experience, and publication record; clear intention to pursue aging research; career potential in behavioral geriatrics research; research career development plans; proposed research; appropriateness of selected advisor(s) for proposed plans; and environment. The initial review will result in recommendations for consideration by the National Advisory Council of the National Institute on Aging. Applications recommended for approval by the Advisory Council will be considered for funding on the basis of the overall merit of the proposal as determined by the Gerontology/-Geriatrics Review Committee, relevance of the proposal to the research objectives of the Institute, and availability of funds. FOOTNOTES: 1/ This program is described in the Catalog of Federal Domestic Assistance No. 13.866, Aging Research. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to Health Systems Agency review. 2/ See "Health Behaviors and Aging: Behavioral Geriatrics Research, NIH Guide for Grants and Contracts, Vol 12, No. 11, November 11, 1983. **THE MAILING ADDRESS GIVEN FOR SENDING APPLICATIONS TO THE DIVISION OF RESEARCH GRANTS OR CONTACTING PROGRAM STAFF IN THE WESTWOOD BUILDING IS THE CENTRAL MAILING ADDRESS FOR THE NATIONAL INSTITUTES OF HEALTH. APPLICANTS WHO USE EXPRESS MAIL OR A COURIER SERVICE ARE ADVISED TO FOLLOW THE CARRIER'S REQUIREMENTS FOR SHOWING A STREET ADDRESS. THE ADDRESS FOR THE WESTWOOD BUILDING IS: 5333 Westbard Avenue Bethesda, Maryland 20816 Vol. 18, No. 22, June 30, 1989 - Page 8 FULL TEXT OF RFAs FOR ONLINE ACCESS ANNOUNCEMENT - REQUEST FOR RESEARCH APPLICATIONS: RFA RFA-HD-03 P.T. 34; K.W. 1002058, 0775000, 0413002 ROLE OF PROTO-ONCOGENES IN MAMMALIAN DEVELOPMENT NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT Application Receipt Date: October 11, 1989 The Genetics and Teratology Branch (GTB) of the Center for Research for Mothers and Children (CRMC) of the National Institute of Child Health and Human Development (NICHD) invites research grant applications for studies on the role of proto-oncogenes in mammalian development. By issuing this request for applications (RFA), the Branch is encouraging investigators' interest in a research emphasis area important to the Institute's mission. BACKGROUND The relationship between cell growth and cell differentiation has been and remains a central question in developmental biology. While growth and differentiation are mutually exclusive in some organisms, their relationship is far more complex in mammalian species. Several independent observations indicate that the same molecules that regulate cell growth in mature organisms are also active during embryonic development. Recent scientific investigation has unveiled an increasing number of molecules that play a role in development. Among them are several "molecular families", one of which includes growth factors and their receptors. Intriguing studies with platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and both alpha- and beta-transforming growth factors (TGFs) suggest that these molecules and their specific receptors are developmentally regulated. The products of proto-oncogenes, the cellular homologues of viral oncogenes, have extensive homology, and in some cases identity, with several growth factors or growth factor receptors. These observations suggest that proteins encoded by proto-oncogenes could play a role in normal development, and aberrations in the expression of such proteins could lead to congenital malformations. Therefore, NICHD encourages studies on the role of proto-oncogenes in mammalian development which could lead to the improved diagnosis and/or prevention of birth defects in the future. The purpose of this RFA is to stimulate and encourage research directed at defining the role of proto-oncogenes in mammalian development. Although it appears that several of the proto-oncogenes have metabolic roles in cellular physiology, embryonic cells may utilize these proto-oncogene products differently under the pressures brought about by morphogenesis and differentiation. Thus, a major focus of this RFA is to examine the embryonic utilization of proto- oncogene products. It is realized that additional descriptive work is needed to expand the field. However, investigators are encouraged to suggest approaches that define functional roles for proto-oncogene products during mammalian development. Such research should be limited to non-human mammals, specifically mice. Proposals on other non-human mammalian species could be considered following investigator discussion with Institute staff prior to submission of applications. This initiative has important implications for both basic science and clinical studies. The information expected from the investigation of the role of proto-oncogenes in mammalian development will further our understanding of the specific molecules that are important in that process. In addition, underlying principles that direct normal patterns of growth, differentiation and morphogenesis and against which aberrations of these processes can be understood will be further defined. In a clinical context, these studies provide the basis for an improved understanding of the possible causes of birth defects and other developmental abnormalities that lead to early embryonic wastage and spontaneous abortion. In this regard, understanding the role of proto-oncogenes in mammalian development, particularly during early postimplantation, will be especially valuable since it is thought that a large number of reproductive failures in humans occurs shortly after implantation. RESEARCH GOALS The primary goal of this RFA is to support a group of projects that are devoted to the investigation of the role of proto-oncogenes during mammalian development. It is expected that the latest molecular genetic technologies will be employed, including the generation of appropriate reagents and the possible production of either chimeric or transgenic animals. Particular program interest includes, but is not limited to, such issues as: o Identification of new proto-oncogenes whose expression is developmentally regulated o Specific localization of proto-oncogene expression during development o Localization of proto-oncogene products during development could include both tissue-specific expression in a defined temporal sequence and cell-specific expression within a tissue. In addition, intra-cellular localization, or changes in such localization during development suggesting possible functional changes, are of interest. o Generation of anti-sense constructs to be used for the direct investigation of developmental function o Investigation of changes in chromatin structure of endogenous proto-oncogenes during development o Evaluation of changes in DNA methylation patterns during the developmental expression of proto-oncogenes o Characterization of DNA sequences that could confer developmental specificity to proto-oncogenes and comparison of such sequences to DNA sequences known to confer such developmental regulation on other genes and gene families o Use of embryonic stem (ES) or embryonal carcinoma (EC) cells as means of investigating in vitro expression of proto-oncogenes during the differentiation of early embryo-equivalent cells o In vitro mutagenesis of proto-oncogene constructs and introduction into ES/EC cells for functional evaluation during differentiation o Generation of chimeric/transgenic animals containing modified proto-oncogene constructs to investigate developmental expression and function o Identification of cellular factors responsible for the developmental regulation of proto-oncogenes o Investigation of a possible proto-oncogene role in the etiology of known developmental mutants o Possible reversal of a developmental aberration by introduction of an appropriate and expressible proto-oncogene construct MECHANISM OF SUPPORT Applications in response to this RFA will be funded through the traditional individual research award program of NICHD. This announcement is for a single competition with the deadline for receipt of applications of October 11, 1989. The earliest possible start date for grants would be April 1990. It is anticipated that four (4) grants will be awarded under this program, contingent upon receipt of a sufficient number of meritorious applications and the availability of funds. REVIEW PROCEDURES AND CRITERIA Applications will be reviewed by NICHD staff for responsiveness to the RFA. Applications judged to be nonresponsive will be returned. The applicant may resubmit the application and have it assigned for review in the same manner as unsolicited grant applications. An application will be considered nonresponsive to this RFA if it is identical to one already submitted to the NIH for review, unless the previous application is withdrawn. Responsive applications may be subjected to a triage by a peer-review group to determine their scientific merit relative to the other applications received in response to this RFA. NIH will withdraw from competition those applications judged to be noncompetitive and notify the applicant and institutional business official. Those applications judged to be competitive will be further evaluated for scientific/technical merit by a review group convened solely for this purpose by the Scientific Review Program, NICHD. Criteria for the initial review include the significance and originality of research goals and approaches; the feasibility of research and adequacy of the experimental design; the research experience and competence of the investigator(s) to conduct the proposed work; the adequacy of investigator(s) effort devoted to the project; and the appropriateness of the project duration and cost relative to the work proposed. Following review by the Initial Review Group, applications will be evaluated by the Institute's Advisory Council for program relevance and policy issues before awards for meritorious proposals are made. APPLICATION PROCEDURE Applications should be submitted on Form PHS 398 (rev. 10/88), available in business or grants offices at most academic research institutions or from the Division of Research Grants, NIH. The phrase PREPARED IN RESPONSE TO RFA 89-HD-03 THE ROLE OF PROTO-ONCOGENES IN MAMMALIAN DEVELOPMENT should appear in item 2 of the face page. The RFA label available in the 10/88 version of Form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. The original and four (4) copies should be sent to: Application Receipt Office Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, Maryland 20892** In addition to the copies sent to the Division of Research Grants, two (2) copies of the application should be sent to: Laurance Johnston, Ph.D. Scientific Review Program National Institute of Child Health and Human Development Executive Plaza North, Room 520A Bethesda, Maryland 20892 Any inquiries about this RFA should be directed to: Joel M. Schindler, Ph.D. Genetics and Teratology Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development Executive Plaza North, Room 643C Bethesda, Maryland 20892 (301) 496-5541 This program is described in the catalog of Federal Domestic Assistance No. 13.865, Research for Mothers and Children. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC241), and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to review by a Health Systems Agency. REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS: RFA-NIH-NIAID-89-AI-18 NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS): OPPORTUNISTIC INFECTIONS P.T. 34; K.W. 0715008, 0740020, 0755025, 0715125, 1002008, 1003006 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Letter of Intent Date: August 1, 1989 Application Receipt Date: December 8, 1989 The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for the establishment of National Cooperative Drug Discovery Groups for the Treatment of Acquired Immune Deficiency Syndrome (AIDS): Opportunistic Infections (NCDDG-OI). There are no present plans to reissue this Request for Application (RFA) at any future time. The NIAID intends to invite competitive renewal applications upon expiration of the initial funding period, contingent on the continued availability of funds for this purpose. LETTER OF INTENT Prospective applicants are asked to submit by August 1, 1989, a letter of intent that includes a descriptive title of the overall proposed research, the name and institution of the Principal Investigator, a title for each component research project and brief descriptions of the proposed projects. Names of prospective project leaders and other key investigators and their respective responsibilities should be included (maximum of two pages). The letter of intent is requested in order to provide an indication of the number and scope of applications to be reviewed and in order to allow early preparations for review, as well as to promote early interactions between applicants and NIAID staff. The letter of intent does not commit the sender to submit an application, nor is it a requirement for submission of an application. The letter of intent should be sent to: Dr. H. S. Allaudeen Targeted Drug Discovery Section Developmental Therapeutics Branch AIDS Program National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard Bethesda, MD 20892 Telephone Number: (301) 496-8197 I. BACKGROUND AND SUMMARY The Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys the body's capacity to defend itself against a variety of infections. Opportunistic infections (OIs) are the pathologic consequence of AIDS; they are the most frequent causes of morbidity and mortality in AIDS patients. OIs are the principal cause of hospitalization of HIV- infected individuals. The estimated total medical costs of the patients in the U.S.A. alone will be $21 billion by 1991. Individuals infected with HIV are susceptible to a range of protozoal, fungal, viral, and bacterial infections. According to the reported frequencies of opportunistic diseases, the major pathogens are Pneumocystis carinii, Candida albicans, herpesviruses (CMV, HSV, VZV) and Mycobacterium avium. The actual incidence of opportunistic infections in HIV-infected individuals may be higher than the reports would indicate, as there are inherent problems in diagnosing and recording these infections. The following is a brief description of major pathogens, currently available therapies, and deficiencies in the clinical management of OIs in AIDS patients. Pneumocystis carinii pneumonia (PCP) is the most serious infection in AIDS patients; between 60 and 80% of AIDS patients will develop this complication. In the past, approximately 90% of untreated individuals died from this infection. Recent studies, based on the phylogenetic analysis of Pneumocystis 16S-like-RNA, indicate it to be a fungus. Trimethoprim/sulfamethoxazole (TMP/SMX) and parenteral pentamidine isethionate are used as initial therapy. Particularly in AIDS patients, TMP/SMX treatment is associated with the development of hypersensitivity reactions and a high frequency of adverse reactions. Recently, the Food and Drug Administration (FDA) has given investigational new drug approval to test aerosolized pentamidine in the prophylaxis of PCP. In the United States, 15 - 68% of the adult population are seropositive for Toxoplasma gondii antibodies. In immunocompromised individuals, reactivation of the pathogen leads to encephalitis, which is fatal if untreated. AIDS patients who are known to have antibodies to T. gondii are at significant risk for developing toxoplasmic encephalitis. At least 30% of AIDS patients who are seropositive for T. gondii will ultimately develop the disease. Current treatment is the combination of pyrimethamine and sulfadiazine. However, the treatment is limited by toxicity and lack of efficacy against the latent cystic form of the parasite. Thus, the relapse rate is high if therapy is discontinued. Recent studies suggest that clindamycin, in combination with pyrimethamine, may be effective against cerebral toxoplasmosis in AIDS patients. Cryptosporidium can cause enterocolitis and diarrhea in humans, malnutrition, and death. Some of the known antiprotozoal and antifungal agents, such as trimethoprim/sulfamethoxazole, pentamidine, ketoconazole and metronidazole, are ineffective against cryptosporidiosis. Fungal infections account for more than 50% of the opportunistic pathogens seen in AIDS patients. Candida albicans is the most common pathogen (80% of fungal isolates). Candida species often cause oral and pharyngeal thrush (mucosal candidiasis). Esophagal candidiasis is also common, but disseminated infection is rare. Cryptococcosis develops in 6 - 13% of patients with AIDS. Recently, there has been an increase in the reported cases of disseminated histoplasmosis caused by Histoplasma capsulatum in patients with AIDS with a history of residence or travel in endemic areas. Current management of fungal infections in AIDS patients has many problems. The diagnosis is often imprecise. The most common therapy is amphotericin B (AMB); sometimes, parenteral AMB is administered in combination with 5- flucytosine. Oral azoles, such as ketoconazole and fluconazole, are currently under study in AIDS patients. AMB is toxic, and continued therapy is often required. Some of the recent fungal isolates are not susceptible to AMB. AMB is only partly effective against coccidioidomycosis. Therefore, there is a need for more selective antifungal agents. Mycobacterium avium complex (MAC) is the most common cause of bacterial infection in AIDS patients. It is an intracellular pathogen that is characteristically resistant to many antituberculosis agents. Thus, it is essential to identify antimycobacterial agents which can penetrate cells, particularly macrophages. MAC is resistant to all standard antituberculosis drugs except ethambutol. Other agents that are effective in vitro against MAC include ansamycin, clofazimine, cycloserine, amikacin, ethionamide, imipenem and ciprofloxacin. Unfortunately, these agents are not bactericidal at concentrations achievable in plasma. Recent studies suggest that combinations of antimycobacterial agents with immunomodulators, such as tumor necrosis factor (TNF), may be useful for treatment of MAC infections. In summary, most opportunistic infections in AIDS patients, especially Pneumocystis pneumonia and cryptococcal meningitis, are life-threatening if diagnosis and treatment are delayed. Others, such as CMV, HSV, and Candida may cause severe morbidity. The management of OIs in AIDS patients is often difficult and complicated for various reasons: (a) they often present with simultaneous OIs; (b) the pathogens may develop resistance to conventional therapies; and (c) the patients are more susceptible to drug-related toxic reactions. It is important to recognize that most of the currently available therapies against the OIs in AIDS patients either lack efficacy or have potentially serious side effects. The severity and long- term consequences of the opportunistic infections underscore the need for more selective and potent therapeutic agents against them. In addition, there is a crucial need for studies on prophylaxis and maintenance therapy for control of persistent and latent infections. II. OBJECTIVES AND SCOPE NIAID wishes to stimulate research efforts leading to the discovery of agents effective in the treatment as well as prophylaxis of OIs in AIDS patients. No clinical trials will be supported. Research efforts may be directed, but are not restricted, towards controlling infections caused by the following pathogens: Pneumocystis carinii, Cryptosporidium spp., Toxoplasma gondii, Candida spp., Cryptococcus neoformans, Histoplasma capsulatum, Mycobacterium avium and M.tuberculosis. It is the intent to support at least one research effort for each major pathogen. No more than one research project can be supported to study viral opportunistic pathogens such as CMV. Research considered responsive to this RFA may include, but is not necessarily restricted to, the following: o Studies to identify and characterize molecular targets in opportunistic pathogens that may be exploited in discovering selective therapeutic agents. o Studies leading to understanding the biochemical differences between the selected pathogen and host cells. For example, isolation and characterization of certain key enzymes in P. carinii or C. albicans (from the organisms or recombinant expression systems) and identification of compounds that selectively inhibit the enzymes from the pathogen. o Molecular genetic studies to identify differences between the pathogens and mammalian cells; studies to exploit the differences to identify selective therapeutic agents. o Synthesis of compounds that will selectively interact with specific molecular targets. o Establishment and utilization of assay systems (biochemical, biological) for selected molecular targets of the opportunistic pathogens to identify active agents in synthetic chemicals and biologicals including natural products. o Development of innovative animal models that may be useful for the evaluation of in vivo efficacy of agents active in vitro. Examination of differences in therapeutic efficacy between the normal and immunocompromised animals. o Studies to examine the response of animals with single or multiple infections to combination therapies and to determine potential adverse or synergistic effects of combination therapies. In addition, the following may be considered as a frame of reference in identifying areas for future investigations. o Some of the pathogens causing opportunistic infections in AIDS patients are intracellular parasites. Therefore, is the ability of potential antimicrobial agents to enter cells, particularly into macrophages, an important requirement for selection of agents for further preclinical development? o Since AIDS patients have diminished ability to eliminate the microbes, is it essential to select out the microbicidal agent(s)? o Recent reports point out the emergence of AZT- resistant strains of HIV in patients undergoing long-term treatment with the drug. In addition, the emergence of acyclovir-resistant HSV and ganciclovir-resistant CMV in AIDS patients treated with these drugs also has been observed. These observations have important implications in the future management of these infections. There is increasing concern over the emergence of drug resistant strains of other pathogens causing opportunistic infections in AIDS patients. This phenomenon emphasizes the need to identify and develop agents active against the strains of pathogens that may become resistant to the currently available drugs to treat the infections. The above-mentioned areas of investigations are representatives of future possibilities. Investigators are encouraged to explore other avenues to identify potential therapeutic agents. III. MECHANISM OF SUPPORT A. Awards will be made as COOPERATIVE AGREEMENTS. NIAID, in awarding the Cooperative Agreement, anticipates substantial staff involvement during performance of the award. The nature of NIAID staff assistance to the awardees is described in Section VIII of this RFA under "TERMS OF AWARD: NATURE OF PARTICIPATION OF NIAID STAFF". There is no intent, real or implied, for NIH staff to direct Group activities or to limit the freedom of investigators. The interaction of academic and non-profit research institutions with commercial (including industrial) organizations and Government is encouraged to favor the efficient invention of new entities and strategies for AIDS treatment and to facilitate their subsequent development to clinical trial. B. NIAID has set aside $3.5 million total costs for the first year of funding. The starting date for the initial annual period will be on or before June 1990. When the applicant institution is outside the United States, awards will be limited to three years. When the applicant institution is within the United States, the request for funding may be up to five years even if the application contains research projects in a foreign country. C. Awards will be made to successfully competing Groups rather than to the individual scientists or institutions comprising the Group. Support of all Group activities will be coordinated through a Central Operations Office located within the applicant organization. Each award will be made only to the Principal Investigator's institution. D. Under the Cooperative Agreement, a negotiated partner relationship between the recipient of the award and NIAID exists in which the Group is responsive to the requirements and conditions set forth in the RFA. Specifically, the Principal Investigator defines the details for the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close coordination, cooperation, and participation of NIAID staff in all aspects of scientific and technical management of the project in accordance with the terms formally negotiated and mutually agreed upon prior to the award. It is presently envisioned that the NIAID will be actively engaged in the coordination of all components, including assisting the awardees in: membership in the Group; collaborative participation in data analysis and reporting; prior approval of changes of key personnel including the Principal Investigator or Project Leaders; retention of the option to withhold support if a Project Leader withdraws from the Group and a suitable replacement of key personnel is not obtained. E. All policies and requirements that govern the grant program of the U.S. Public Health Service and the National Institutes of Health (NIH) apply. F. Although this program is provided for in the financial plans of NIAID, the award of Cooperative Agreements pursuant to this RFA is also contingent upon the continuing availability of funds for this purpose. IV. DEFINITIONS COOPERATIVE AGREEMENT - An assistance mechanism in which substantial NIAID programmatic involvement with the recipient organization during the performance of the planned activity is anticipated. CORE COMPONENT - Laboratory facilities for equipment and services which shall be shared by two or more projects of the NCDDG. Examples of core components are: biochemical studies, screening studies, scale-up synthesis of drugs (ten grams or less). The core can be defined as any project with established techniques and assays which perform a service function or results in an economy of effort and savings in the overall costs of the NCDDG. NATIONAL COOPERATIVE DRUG DISCOVERY GROUP (NCDDG) - In this RFA the terms, NATIONAL COOPERATIVE DRUG DISCOVERY GROUP, NCDDG, and "Group" are synonymous. A number of laboratory research projects representing diverse scientific disciplines and organizations join together under a single Principal Investigator and function as a unit with a common goal: the conceptualization, invention, and evaluation of new entities and strategies for treatment of AIDS-associated opportunistic infections. NEW DRUG - In the context of the NCDDG-OI program, the term "drug" is used broadly to encompass new synthetic agents, natural and biological products as novel therapeutic strategies or inventions designed to effectively treat OIs in AIDS patients. DISCOVERY - The term "discovery" is used explicitly to limit activities of the NCDDG to preclinical identification, design and development of new entities. PROJECT LEADER - The leader of one of the scientific research projects of the NCDDG. PRINCIPAL INVESTIGATOR - The person who assembles the NCDDG, assembles a single application with the information provided by the Project Leaders and submits the application in response to this RFA and who is responsible for the performance of the Group as a whole and each of the Project Leaders. The Principal Investigator may lead one of the research projects of the Group and coordinate Group activities scientifically and administratively. The Principal Investigator's (awardee) institution establishes and operates the Central Operations Office that funds Group members and is legally and fiscally accountable for the disposition of funds awarded. NIAID NCDDG PROGRAM DIRECTOR - A member of the NIAID extramural staff who coordinates NIAID's participation in the NCDDG Program. NIAID SCIENTIFIC COORDINATOR - A member of the extramural staff of the NIAID who functions as a peer with the Principal Investigator and Project Leaders and facilitates the partnership relationship between NIAID and the Group. INVENTION - A new drug or innovative treatment that is or may be patentable under Title 35 of the United States Code. ARBITRATION PANEL - A group composed of the Principal Investigator or Project Leader of a particular NCDDG as the "Group" designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two. The interaction of this panel is detailed in Section VIII, TERMS OF AWARD. V. COMPOSITION OF AN NCDDG-OI A. The NCDDG-OI will consist of the following: 1. Principal Investigator; 2. Project Leaders, each to head a research project. The research projects will utilize diverse scientific disciplines or alternative disciplines that are appropriate to the realization of Group objectives (e.g., microbiology, biochemistry, humoral immunology, cellular immunology, structural biology, biophysics, biochemistry, medicinal chemistry, organic chemistry, etc.). Interdisciplinary projects are encouraged; and 3. A Scientific Coordinator designated from the NIAID extramural staff. 4. (OPTIONAL) core components which would provide for laboratory facilities, equipment and services to be shared by two or more projects. It may also include support for the costs of administration, purchasing and secretarial services. Items described above that are included in the institution's indirect cost rate are subject to negotiation, based on their applicability as direct or indirect charges. B. The Principal Investigator, in addition to providing scientific and administrative leadership, may have a research project. Project Leaders will be directly responsible to the Principal Investigator. The formation of the Group, the application in response to this RFA, the overall management of the Group, and the allocation of funds to the various laboratory projects will be the responsibility of the Principal Investigator and the Principal Investigator's institution in accordance with PHS policies. C. The composition of the Group and its research projects should depend on the talents required to accomplish its scientific and technical objectives as perceived by the Principal Investigator and Project Leaders. The major consideration in structuring an NCDDG should be the mobilization of maximum intellectual strength and the ability to carry out the proposed research. D. An individual scientist may be proposed as a Project Leader by more than one applicant as part of a CORE COMPONENT. Project Leaders who do not have a core function will not be supported by more than one Cooperative Agreement awarded under this RFA unless the research is clearly delineated in separate NCDDG applications. Individuals currently supported under an existing AIDS NCDDG or other NCDDG may be funded under this RFA as long as there is no scientific or budgetary overlap in funded activities. E. An NCDDG may have more than one project from one institution. However, the varied talents and commitment required for effective drug discovery are not usually all present in one institution, and it is anticipated that the Project Leaders within a Group will be from several institutions. F. A minimum of two but no maximum number of research projects per Group is stipulated. However, the Principal Investigator could experience difficulty in providing the desirable level of guidance and Project Leaders might communicate and collaborate less efficiently if the Group were to contain more than five or six research projects, including the Principal Investigator's project. G. In forming Groups, Principal Investigators should remain cognizant of the need for communication, including regular meetings of the members. While it is not a requirement of this RFA, the formation of Groups on a geographically regional basis may be advantageous. This is a particularly important factor to be considered by applicants from outside the United States or if the applicant proposes laboratory projects in foreign countries. H. An NCDDG may be formed by scientists from academia, non- profit institutions, and/or commercial organizations. The active participation of industry is encouraged because it will allow this segment of the scientific community to contribute its intellectual and material resources. VI. RESEARCH GOALS AND SCOPE A. The goals of the NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR THE TREATMENT OF OPPORTUNISTIC INFECTIONS are: 1. The conceptualization, discovery and preclinical development of drugs and strategies designed to effectively treat OIs in individuals infected with the human immunodeficiency virus; 2. The conduct of biological, biochemical, and pharmacological studies leading to selection of potential therapies; and 3. The recommendation of therapies, entities or strategies for development in clinical trials. B. Applications for an NCDDG-OI should stress creative approaches to the discovery of effective therapies to treat opportunistic infections and should emphasize the following: 1. specific objectives of the proposed NCDDG-OI; 2. research approaches to the realization of objectives and the provision of comprehensive information (including citations) in support of the rationale(s) for the proposed approaches; and 3. the scientific and technical areas of expertise (Project Leaders) required to attain Group objectives and the leadership ability of the Principal Investigator. VII. PATENT COVERAGE Since the discovery of agents active against OIs in AIDS patients is the objective of this effort, and since active involvement by industrial laboratories is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. With multiple institutions involved, the patent situation could be complicated. Each applicant Group must, therefore, provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. In addition, each Group must provide a detailed description of the procedures to be followed for the resolution of legal problems which may develop. All Group members can be full partners in the research and in any inventions resulting therefrom. The specific patenting arrangements among the institutions may vary, and could include joint patent ownership and exclusive licensing arrangements. Applicants are encouraged to develop an arrangement that is most suitable for their own particular circumstances. The proposed patent plan among the institutions comprising the Group MUST be included along with the application. This patent agreement signed and dated by the organizational officials authorized to enter into patent arrangements for each Group member and member institution will be forwarded for filing with Dr. Margaret Johnston, Chief, Targeted Drug Discovery Section, DTB, AIDS Program, 6003 Executive Boulevard, NIH, Bethesda, MD 20892. VIII. TERMS OF AWARD: AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF PARTICIPATION OF NIAID STAFF Assistance via Cooperative Agreement differs from the traditional research grant in that, in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. However, the applying Group must define its objectives and approaches in accord with its own interests and perceptions of novel and exploitable approaches to the discovery of effective agents active against OIs in AIDS patients and must develop the details of the research design following the guidance given in this RFA. It is the primary responsibility of the Principal Investigator to clearly state the objectives and approaches of the Group, to plan and conduct the research stipulated in the proposal, and to ensure that the results obtained are analyzed and published in a timely manner. The data obtained will be the property of the awardee. NIAID shall participate as a member of the Group and shall be represented by a Scientific Coordinator. The Coordinator shall be selected from the Developmental Therapeutics Branch of the AIDS Program and appropriate Branches of the Microbiology and Infectious Diseases Program of the NIAID. During performance of the award the NIAID Scientific Coordinator may provide appropriate assistance, advice, and guidance by participating in the design of group activities; advising in the selection of sources or resources, replacement of staff, etc.; coordinating or participating in collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. However, the role of NIAID will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities outlined below will be reached by consensus of the Group and that NIAID staff will be given the opportunity to offer input to this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator. A. Group Activities, Development of Research Protocols and Evaluation of Results 1. The Principal Investigator, Project Leaders, and the NIAID Scientific Coordinator will meet periodically to review progress, plan and design research activities, and establish priorities. The frequency of meetings (not less than two per year) shall be determined by the Principal Investigator who will be responsible for scheduling the time and place (generally at one of the performance sites), notifying the Scientific Coordinator 60 days prior to the meeting date, and preparing concise proceedings or minutes which will be delivered to the members of the Group including the Scientific Coordinator within sixty days of the meeting. NIAID Scientific Coordinator will not chair Group meetings. In addition to these two meetings, one meeting each year will be held at the NIH Bethesda (or at a site designated by NIAID) during which all Principal Investigators and Project Leaders will present significant findings in symposium format. It is expected that selected NIH staff, members of established committees and advisory boards, and others active in the process of discovery and development of therapies for opportunistic infections will be invited to this meeting. The Principal Investigator will have control over the data and results presented by the Group. Funds for attendance of these three required meetings should be included in the budget for each research project. A critical determinant of Group success will be the degree of communication among its members. Therefore, additional informal meetings among all participants, as well as regular telephone and written communication, will be important. 2. The NIAID Scientific Coordinator, like other Group members, may suggest studies within the scope of the Group's objectives and research activities; may present to the Group experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design and execution of experiments as agreed to by the Group; and may participate in the analysis and publication of results. 3. The NIAID Scientific Coordinator may assist the Group or other individual members in research planning, particularly with respect to: a. reduction of duplication of efforts conducted in other extramural projects; b. provision of needed resources and information that may not be otherwise available to the Group; and c. provision of data from testing conducted in resource contract laboratories. 4. The NIAID Scientific Coordinator may assist the Groups by providing them with compounds for initial testing and for confirmatory testing. In testing compounds supplied by the NIAID, the Groups agree to abide by any confidentiality agreement between the NIAID and a third party who has supplied the compounds for testing through NIAID. B. NIAID Assistance in Implementation and Management of Research Activities NIAID staff, through a designated Scientific Coordinator, may serve as a resource for information, laboratory testing, and biological supplies (e.g., animals), when such resources are not a normal requirement of the Group's day-to-day research activities but may be required on an occasional basis. The following is a list of some resources that might be supplied if they become desirable during performance, are not anticipated as a continuing need, and may be available from the NIAID: 1. Reference compounds for standardization of test systems, as analytical standards and for related purposes. 2. Materials for biological testing. 3. Laboratory testing capacity, whenever appropriate and possible, in a current contract-based preclinical therapy- related laboratory testing program or other NCDDGs. The Groups are expected to provide sufficient test material for such testing. 4. Searches of computer files of chemical structures and biological activity, if requests for such searches are sufficiently focused to avoid excessive costs. Information given to an NCDDG will be restricted by any standard confidentiality agreements between the Government and suppliers of test materials to the Government. 5. Experimental animals, when the occasional need arises in Groups whose main research activities do not require these materials on a regular basis. Groups whose experimental approach involves studies that require animals on a regular basis must budget for costs to be paid from award funding. 6. Computer processing and statistical evaluations if costs are not excessive. 7. Networking with other NIH Staff, NCDDGs, other collaborators and other government and non-government employees who may provide guidance, expertise or resources to facilitate development of therapies identified by the Group. It is understood that the Government provides its consulting and testing services in the interest of promoting experimental anti-infective agents through preclinical and clinical testing and development in the most expeditious fashion, and that newly marketed agents that have utilized this service will be offered to the public at a reasonable cost. C. NIAID Assistance in the Collection and Analysis of Data, Procedures for Submission of Results to NIAID, and Preparation of Group Findings for Presentation and Publication In addition to the special reports and stipulations described below, reporting requirements will be identical to those currently in existence for awardees of traditional NIH research project grants. 1. The principal end product of NCDDG-OI activities will be the discovery of new entities and strategies for development to clinical trials for AIDS-associated OIs. Subsequent developmental work through private resources is encouraged. Alternatively, the Group may recommend that development be sponsored by NIAID. In the latter case, it will be necessary for the Principal Investigator, appropriate Project Leaders, and NIAID to collaborate in the analysis, summarization, preparation, and presentation of data to the appropriate NIAID staff. 2. NIAID will retain the option to cross-file or independently file an application for investigational clinical trial; e.g., an Investigational New Drug Application (INDA) to the United States Food and Drug Administration of any invention resulting from these NIAID- supported Cooperative Agreements. Reports of data generated by the Group or any of its members required for inclusion in INDAs and Clinical Brochures and for cross-filing purposes will be submitted by the Principal Investigator to the Scientific Coordinator upon request. Such reports will be in final draft form and include background information, methods, results, and conclusions. They will be subject to approval and revision by NIAID and may be augmented with test results from other Government-sponsored projects prior to submission to the appropriate regulatory agency. 3. The Government, via the Program Director or designated Scientific Coordinator, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. Information obtained from the data may be used by the Scientific Coordinator for the preparation of internal reports on the Group's activities. However, the applicant will retain rights to the data, and timely publication of major findings is encouraged. Publication or oral presentation of work done under this agreement is the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIAID support. D. Inasmuch as certain activities under "TERMS of AWARD: NATURE OF PARTICIPATION OF NIAID STAFF" require approval by NIAID staff during performance of this Cooperative Agreement (specifically, reports intended for inclusion in INDAs and Clinical Brochures, change in Principal Investigator or Program Leader, redistribution of biological materials received through the Scientific Coordinator and dissemination of research findings resulting from the use of these materials), NIAID will establish an arbitration process to resolve any differences of opinion. An arbitration panel, composed of one Group designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two, will be formed to review any scientific or administrative issue that is significantly restricting progress. This arbitration process in no way affects the right of an award recipient to appeal selected post award administrative decisions in accordance with HHS, PHS, and NIH regulations. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. E. The special "TERMS OF AWARD: NATURE OF PARTICIPATION OF NIAID STAFF" described in this section are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74, and other HHS, PHS, and NIH grant administration policy statements. IX. MINIMUM REQUIREMENTS FOR APPLICATION Applicants seeking funding as a NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR THE TREATMENT OF OPPORTUNISTIC INFECTIONS must meet the following requirements: The application must be from a Group and must: A. Name a single Principal Investigator who is an employee of the applicant institution and who will be responsible for the application, for Group research activities, and for the support of Group activities through a Central Operations Office; B. Identify the single applicant organization (grantee institution) that will provide the Central Operations Office and be legally and financially responsible and accountable for the use and disposition of funds awarded on the basis of this RFA; show availability of personnel and facilities capable of performing and supporting the administrative functions of the NCDDG-OI; C. Identify the Group as having an approach that should be reviewed as being comprehensive, immunological, biological, or synthetic in its approach for the design of new treatments for OIs in AIDS patients; D. Provide a description of the Group's plan for assuring adequate patent coverage of new inventions that may issue as a result of Government funding of the proposed work; NOTE: A formal statement of Patent Agreement among all Group members and their institutions, as well as a detailed description of procedures to be followed for the resolution of legal problems which may develop, signed and dated by the organizational official authorized to enter into patent arrangements for each Group member and member institution, is to be submitted with the application. E. Provide a clear, concise plan in narrative and diagrammatic form that depicts the interrelationships among the members of the Group and the contribution of each to fulfillment of Group objectives; provide an organizational chart of the Group showing the name, organization, and scientific discipline of the Principal Investigator and Project Leaders; provide an organizational chart for each laboratory project within the Group showing relationships among the key personnel; F. Provide a plan to assure the maintenance of close collaboration and effective communication among members of the Group that includes letters of commitment to this plan and a letter accepting the participation of NIAID Scientific Coordinator; G. Demonstrate that each component research project contributes to the attainment of the Group's objectives and that each has available the professional and technical personnel to permit efficient and successful conduct of the proposed research; show that total personnel of the Group are sufficient in quality and quantity to assure successful conduct of the proposed research; and NOTE: Other activities which are essential to maintaining or achieving the objectives of the stated research projects (e.g., large scale production of reagents, animal maintenance) should be included as subcontracts under the budget for core resources. H. Demonstrate that each component laboratory project and the Group as a whole have available the facilities required for conduct of the proposed research; demonstrate that appropriate biohazard facilities and safety procedures are in place for activities involving HIV and other pathogens and pathogen-producing cell lines as outlined in The Federal Register, Volume 49, Number 201, Tuesday, October 16, 1984, p. 40556 (Attachment 2); include a copy of the Institutional Safety Manual for each proposed laboratory project. X. REVIEW METHOD AND PEER REVIEW CRITERIA APPLICATIONS WHICH ARE NOT RECEIVED AS A SINGLE PACKAGE FROM THE PRINCIPAL INVESTIGATOR AND WHICH DO NOT CONFORM TO THE INSTRUCTIONS CONTAINED IN PHS 398 (rev. 10/88) APPLICATION KIT WILL BE JUDGED NON-RESPONSIVE AND WILL BE RETURNED TO THE APPLICANT. Applications will be reviewed by NIAID staff to determine administrative and programmatic responsiveness to this RFA; those judged to be non-responsive will be returned to the applicant without review. Those applications that are complete and responsive may be subjected to a triage by an NIAID peer review group to determine their scientific merit relative to the other applications received in response to this RFA. The NIAID will withdraw from competition those applications judged to be noncompetitive for award and will notify the applicant and institutional business official. Those applications judged to be competitive for award will be further reviewed for scientific and technical merit by a Review Committee convened by the Extramural Activities Program, NIAID, during February 1990. The final level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. REVIEW PROCEDURES AND CRITERIA The application must be directed towards the attainment of the stated programmatic goals (see Section VI, "RESEARCH GOALS AND SCOPE"). The following factors will be considered in the scientific and technical review of the application: A. Relevance of applicant's (Group) objectives to the discovery of new entities and strategies for the treatment of AIDS; B. Scientific and technical significance, originality and uniqueness of proposed research; C. Scientific merit of approaches to realization of objectives; D. Specific competencies of the Principal Investigator and Project Leaders to conduct the proposed work: research experience, competence, commitment, and time availability of Principal Investigator, Project Leaders, and other key personnel; E. Technical merit of proposed methods for producing or obtaining test materials and for their evaluation; F. Technical sufficiency of methods for evaluation of new discoveries, laboratory test systems, models, etc.; G. Administrative experience and competence of Principal Investigator in the development, implementation, and management of comprehensive research programs; H. Plans for effective intra-Group communication and for assuring Group cohesiveness; I. Adequacy of existing physical facilities and resources of the Principal Investigator and Project Leaders including biohazard containment facilities as stipulated in Section IX, "MINIMUM REQUIREMENTS FOR APPLICATION," Part K; J. Documented commitment of institutions represented by Group members; documented capability of Principal Investigator's institution to serve as Central Operations Office for the Group; K. Commitment to accept the participation and collaboration of NIAID staff in accordance with the guidelines outlined under Section VIII, "TERMS OF AWARD: NATURE OF PARTICIPATION OF NIAID STAFF;" L. Mechanism for selecting and replacing key professional or technical personnel using the framework of the RFA; M. Ability of the Principal Investigator and Project Leaders to devote adequate time to the effectiveness conduct of the study; N. Conformance to "MINIMUM REQUIREMENTS FOR APPLICATION" (Section IX). O. Reasonableness of cost XI. METHOD OF APPLYING Before preparing an application, the prospective applicant should carefully read the NIAID Information Brochure on Program Project and Center Grants which is available from Dr. Hortencia Hornbeak at the address below. The Information Brochure contains special instructions for preparing multi-project applications, review procedures, review criteria and other important information. It is important to follow the instructions for preparing the application as outlined in the Information Brochure. Failure to do so may result in an application with insufficient information for appropriate scientific review. Questions regarding instructions in the brochure should be directed to Dr. Hornbeak (address below). Questions regarding responsiveness to the RFA should be directed to Dr. H.S. Allaudeen, telephone (301) 496-8197. o Receipt Date The deadline for receipt of applications is December 8, 1989. Applications received after this date will be considered as not responsive to this RFA and will be returned without review. o General 1. The regular research grant application forms PHS-398 (rev. 10/88) are available at most institutional business offices or from: Office of Grants Inquiries Room 449 Westwood Building Division of Research Grants National Institutes of Health Bethesda, Maryland 20892 2. Submit a signed, typewritten original of the application, including the Checklist, and six signed, exact, single-sided photocopies, in one package to: Division of Research Grants Westwood Building, Room 240 Bethesda, Maryland 20892** The RFA label available in the form PHS-398 (rev. 10/88) must be affixed to the bottom of the face page of the original signed application. Failure to use this label could result in delayed processing of the application such that it may not reach the committee in time for review. 3. TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH THIS RFA: The application form must have "NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR THE TREATMENT OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)" (RFA 89-AI-18) typed on item 2 of the face page of the application form. 4. Prominently label the application according to one of the following categories: a. THIS IS A COMPREHENSIVE NCDDG APPLICATION b. THIS NCDDG APPLICATION IS IMMUNOLOGIC ONLY c. THIS NCDDG APPLICATION IS SYNTHETIC ONLY d. THIS NCDDG APPLICATION IS BIOLOGICAL ONLY e. THIS NCDDG APPLICATION IS A COMBINATION (2): This facilitates assignment of the application to reviewers with appropriate expertise. 5. SUBMIT 18 EXACT COPIES OF YOUR APPLICATION DIRECTLY TO Dr. Hortencia Hornbeak: Chief, AIDS Review Section Program Project and Review Branch National Institute of Allergy and Infectious Diseases Westwood Building, Room 3A05 Bethesda, MD 20892 (301) 496-0123 C. Organization of Application and Suggested Modifications of Form PHS-398 (rev. 10/88) This RFA requires the submission of a single application for the proposed NATIONAL COOPERATIVE DRUG DISCOVERY GROUP. Because of the multi-institutional nature of an NCDDG and the special requirements in this RFA, additional instructions regarding format are contained in the NIAID Information Brochure on Program Project and Center Grants (available from Dr. Hornbeak at the address below). The special requirements of this RFA will also necessitate the following modification. The Introductory Section should apply to the proposed NCDDG as a whole with respect to goals, objectives, and overall research plan. The Introductory Section, not to exceed 2 pages, should contain any additional information about the proposed Principal Investigator or his/her institution as evidence of capability to carry out the scientific and administrative duties required in this RFA and the functions of the Central Operations Office. In addition, the Introductory Section must include the following elements (See Section IX of this RFA): 1. the name of a single Principal Investigator in accordance with Section IX, Part A; 2. the name of the single applicant organization that will provide and operate the Central Operations Office in accordance with Section IX, Part B; 3. a statement assuring adequate patent coverage of new inventions that may issue as a result of Government funding in accordance with Section IX, Part D; 4. a statement of acceptance of the provisions of Section VIII, "TERMS OF AWARD: AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF PARTICIPATION OF NIAID STAFF;" 5. a description of the inter-relationships among members of the Group and organizational charts in accordance with Section IX, Part E; and 6. a plan to assure maintenance of close collaboration and effective communication among members of the Group in accordance with Section IX, Part F. XII. INQUIRIES Inquiries of the program aspects of this RFA may be addressed to Dr. H. S. Allaudeen (Section XI Method of Applying). Inquiries regarding matters pertaining to the review of this application should be addressed to Dr. Hornbeak. Inquiries regarding fiscal matters may be addressed to Mr. Thompson. Mr. Gary Thompson Hortencia Hornbeak, Ph.D. Chief, Grants Management Branch Chief, AIDS Review Section Westwood Building, Room 726 Westwood Building, Room 3A05 NIAID, NIH NIAID, NIH Bethesda, Maryland 20892 Bethesda, Maryland 20892 Telephone: (301) 496-7231 Telephone: (301) 496-0123