Subject: NIH GUIDE - RFA HL-91-07 - V20(19) 05/17/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 15 May 91 15:30 EST

Hi Paul,
this is part 3 of 4, May 17, 1991, NIH Guide. Please post to the list
server as :
       RFAHL-91-07.910517
                            Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA HL9107 HL-91-07
 
REQUEST FOR APPLICATIONS
 
RFA:  HL-91-07
 
PROGRAM PROJECTS IN VASCULAR BIOLOGY AND MEDICINE
 
P.T. 34; K.W. 0705015, 0745020, 0745027, 0745070, 0705065
 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  July 31, 1991
Application Receipt Date:  October 15, 1991
 
PURPOSE
 
Vascular Biology and Medicine are of particular interest to the National
Heart, Lung, and Blood Institute (NHLBI) because they serve a bridging
and an integrating function by providing a common ground for studies of
cardiovascular, pulmonary, and blood-related processes.  The purpose of
this initiative is to encourage development of program projects
featuring innovative and interdisciplinary approaches to vascular
biology and medicine.  In particular, combined basic and clinical
collaborative programs are required for translating the rapid advances
in vascular biology into diagnostic, therapeutic, and preventive
interventions for improving vascular health.  This pertains to both the
systemic and pulmonary circulations.  For purposes of this solicitation,
vascular biology is defined as the study of mechanisms of development
and regulation of blood vessels and integration of the knowledge gained
into an understanding of the physiologic dynamics of the vasculature.
Vascular medicine concerns itself primarily with the clinical management
of a wide variety of vascular diseases.  Its objectives are:  the
clinical characterization of all vascular diseases including arterial,
venous, and lymph in the cerebral, coronary, pulmonary, aortic, renal,
and peripheral vascular beds; analysis of the pathogeneses of these
diseases including atherosclerosis, lipid metabolic disorders, systemic
and pulmonary hypertension, peripheral vascular disease, lymphedema,
thrombosis, vasculitis, and vasospastic disorders; and the development
of better diagnostic, therapeutic, and preventive approaches to these
diseases.  Investigators from a variety of disciplines including, but
not limited to atherosclerosis, cardiology, cell biology, hematology,
hypertension, molecular biology, pulmonary medicine, radiology, vascular
biology, vascular medicine, and vascular surgery are encouraged to form
collaborations to meet the goals of the RFA.
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of 'Healthy People 2000,' a
PHS-led national activity for setting priority areas.  This RFA,
'Program Projects in Vascular Biology and Medicine,' is related to the
priority area of Heart Disease and Stroke.  Potential applicants may
obtain a copy of 'Healthy People 2000' (Full Report:  Stock No.
017-001-00474-0) or 'Healthy People 2000' (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington DC 20402-9325 (telephone 202-783-3238).
 
BACKGROUND
 
As recently as the early 1970s, blood vessels were viewed as
semi-dynamic conduits designed to distribute blood flow with some
physical filtering properties allowing for nutrient transport and waste
removal.  Insights into vascular function were predominantly mechanical.
With the development of cellular biology, molecular biology and a
variety of sophisticated techniques, the blood vessel was studied in
much greater detail, and contrary to earlier opinion, was found to have
the properties of a dynamic complex organ.  From early electron
microscopic studies of the endothelium and cell culture studies of
vascular smooth muscle, vascular biology has now evolved into a
multidisciplinary approach to the examination of cell behavior,
primarily endothelial and vascular smooth muscle cells, as well as other
important cells such as the platelet, the lymphocyte, the monocyte, the
macrophage, and the neutrophil.  In vascular biology there is an
emphasis on:  communication, including signal generation, transduction,
and molecular and cellular responses; analysis of the cell cycle in
response to hypertension and atherosclerosis with particular attention
paid to vasoactive factors, vasotropic factors, and factors stimulating
smooth muscle replication; and finally, the genes responsible for
regulating communication and cell cycle behavior.
 
Vascular medicine has become increasingly sophisticated in recent years
with the development of noninvasive vascular imaging technologies, new
drugs such as the thrombolytic agents, and mechanical revascularization
through surgical and angioplasty techniques.  The underlying hypothesis
of this RFA initiative is that progress in vascular medicine can be
enhanced substantially if it is integrated with the science of vascular
biology.
 
PROGRAM PROJECT GRANT
 
A program project grant accommodates the support of a research program
in which a multidisciplinary team of investigators works collaboratively
in a clearly defined area of mutual scientific interest.  In a program
project, achievement of the objectives of the research effort is
facilitated by the sharing of ideas, data, and specialized resources
such as equipment, laboratories, and clinical facilities.  An essential
requirement is a central theme toward which the total scientific effort
is directed and to which each research project relates.  The NHLBI
expects the applicant to define the integrating theme and to develop the
approaches that would be used to accomplish the objectives of the
proposed research program.  The program should not be so global as to
include disparate or unrelated scientific objectives in broad areas.
The theme of a program project might involve, for example, a unifying
concept of biological control, a particular problem common to related
diseases, or a disease process encompassing both basic science and
clinical research efforts.
 
The size of a program project should be carefully considered.  The
program project must be composed of a sufficient number of
scientifically meritorious research projects to permit an efficacious
collaborative effort among the participating investigators.
 
The interrelated research projects included in the program should be
conducted by experienced scientists who have a variety of disciplinary
and specialty backgrounds and who are willing and able to relate to each
other so that new scientific information may be freely exchanged and
effectively utilized by others in the research program.  The program
director must be an established leader in scientific research with
demonstrated capabilities in administration.  The director is expected
to demonstrate exemplary leadership by presenting a cohesive program,
focusing research efforts on a central theme, and eliminating research
projects that are of insufficient quality or those unrelated to the
theme.  The quality of the written grant application and its
cohesiveness, indeed, serve as an indicator of the leadership
capabilities of the director.  Meetings of participating investigators,
who share and evaluate results and new ideas, are essential to the
consolidation of the research projects into a cohesive program.  An
internal advisory committee selected from the participating
investigators in the program can be effective in assisting the program
director in making scientific and administrative decisions.  An advisory
committee composed of outside consultants can be helpful in providing
scientific and organizational advice and assisting the Principal
Investigator in maintaining and monitoring scientific progress.
 
Before preparing an application, potential applicants are urged to
contact the appropriate program administrator, listed under 'Inquiries'
below, for further guidance.
 
OBJECTIVES AND SCOPE
 
For the purposes of this RFA, program project grants are viewed as the
mechanism for facilitating the union between vascular biology and
vascular medicine.  It will provide opportunities for basic and clinical
scientists to interact in a way that will advance understanding in a
variety of vascular diseases in order to promote the development of new
diagnostic, therapeutic, and preventive strategies.  Unlike the usual
program project that has historically been free-standing and autonomous,
the investigators funded through this RFA will be expected to interact
with one another in a dynamic way by networking and in some instances by
collaborating through shared protocols.  To facilitate this, RFA
meetings will be held twice a year to exchange information and to
initiate and sustain collaborative investigations on mutually agreed
upon problems that are impeding progress in the evolution of vascular
biological concepts into clinically relevant research and thence to
patient care.
 
It is the intent of this RFA to provide support for integrating vascular
biology research with vascular medicine investigations in areas that
have previously resisted successful integration, as well as to provide
support for innovative research that transcends traditional vascular
biological investigations.  An emphasis on in vivo work and other modes
of research which facilitate the transition from basic research to
clinical application should be noted.  Concepts derived from basic
studies using in vitro techniques need to be validated for their
relevance to clinical studies of human vascular disorders.  It is
unlikely that proposed basic research studies alone would be considered
appropriate for this initiative.  In vivo testing of accepted concepts
derived from in vitro experiments is appropriate and desirable.
Development of new technologies and methods for use in animal models and
human subjects in order to further facilitate the transition from basic
science to vascular medicine studies is encouraged.
 
It is incumbent upon the Principal Investigator to choose the blend of
basic science and clinical research projects that maximizes the central
priority of the RFA, the integration of vascular biology with vascular
medicine in order to better understand and treat vascular diseases.
 
PROPOSED RESEARCH
 
Examples of research that would be responsive to this RFA are given
below.  These research topics are intended to provide a perspective of
the scope of research that would meet the objectives of this program.
It is not required that all or any of these topics be included in an
application.  Investigators are encouraged to consider other topics
relevant to the goals of this program, as well as collaborations with
investigators outside of their departments and even outside of their
institutions as appropriate.
 
  o  Studies on local and systemic control mechanisms whereby vasoactive
     growth and angiogenic growth factors (e.g., endothelins, cytokines,
     PDGFs, TNFs, and HBGFs) could be evaluated for therapeutic
     potential in efforts to increase vascularization, collateral
     development or vascular architectural remodeling.
 
  o  In vitro and in vivo studies of the interaction of the vessel wall
     with blood components (e.g., neutrophils) with emphasis on the
     adhesion molecules are needed.  The binding sites of neutrophils to
     endothelium may produce a protected microenvironment which is
     inaccessible to serum antiproteases and antioxidants and may be the
     initial sites of injury.
 
  o  The vascular endothelium in culture can be stimulated with
     lymphokines and other agents to change its anticoagulant and
     antithrombotic properties to those of a procoagulant and
     thrombogenic surface.  Do such changes occur in vivo or are there
     protective mechanisms that do not exist in a cell culture system?
     How generalized is such an alteration in endothelial function?  Is
     it reversible?  Is the endothelial dysfunction total or limited to
     a single defect or enzyme system?  How are such changes influenced
     by drugs, diet, and age?  How can one diagnose and evaluate
     endothelial dysfunction?  Might it be an early measure of
     atherosclerosis or thrombogenic potential?
 
  o  Studies on endothelial cell subtype specialization and differential
     expression of surface antigens, receptors, and channels could
     potentially be exploited in treatment by targeting specific
     systemic and pulmonary vascular beds.  Development of techniques to
     attach or internalize marker molecules could be used in conjunction
     with bifunctional "designer" molecules of therapeutic benefit in
     compromised, injured or ischemic beds (e.g., antithrombotic
     reagents in cerebrovascular or coronary vessels).
 
  o  Studies to identify mechanisms involved in altering inter-and
     intracellular transport of substrates, metabolites, or gaseous
     components across endothelial and deeper cell layers in different
     microvascular beds.  If it were possible to achieve tissue
     specificity, such manipulations could be exploited therapeutically
     in a considerable variety of conditions.
 
  o  Development of practical techniques to utilize endothelial cells as
     targets for insertion of regulatory or structural coding sequences
     which could chronically or acutely control expression of beneficial
     cell products (e.g., antioxidants, antiproteases, vasodilators) and
     repopulate injured vessels with genetically "improved" cells.
 
  o  Studies on the development and construction of cell lines, reagents
     and techniques that could provide the means to genetically
     manipulate, ex-or in vivo, endothelial or fibroblastic cells to co-
     or repopulate compromised, denuded systemic or pulmonary vascular
     beds or grafts, with constitutively or inducibly expressed
     beneficial or protective elements.
 
  o  Studies involving hemostatic and thrombogenic mechanisms in the
     neonate are of particular interest.  They may involve genetic and
     developmental defects or acquired problems that create major
     clinical obstacles for the infant and could provide insight into
     the pathogenesis of vascular diseases in adults.
 
  o  Vascular spasm is an important component of vascular disease
     particularly in critical perfusion areas such as the heart and
     brain.  How much of vascular spasm is due to local release of
     stimuli from platelets?  WBCs?  neurogenic components?  breakdown
     of normal vasodilator mechanisms?  Does spasm involve reactions
     that set up a local thrombogenic environment?  How much of spasm is
     a reaction to episodic occlusion by thrombi or emboli?  How can the
     answers to these questions be exploited for therapeutic purposes?
 
  o  Vascular biologic investigations into the nature of vasculitis are
     needed.  Such studies could address the etiologic and pathogenetic
     mechanisms of a variety of vasculitides in the systemic and
     pulmonary vascular beds which could lead to more precise
     therapeutic applications.
 
  o  Research to develop noninvasive high resolution spatial
     localization technologies using nucleic acids, monoclonal
     antibodies or other immunological reagents could facilitate
     identification of sites of impaired vessel integrity, aneurysm,
     proliferation or inflammation.  Coordinated visual and
     spectroscopic modalities and advanced ECHO/Doppler methods would
     also be useful in assessment of specific vascular beds.  For
     example, application of these technologies to the evaluation of the
     pulmonary vasculature could lead to early diagnosis and improved
     management of pulmonary hypertension in the fetus, neonates,
     children, and adults.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.
 
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information should be included in the form PHS 398 in Section 2,
A-D of the Research Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native Americans
(including American Indians or Alaskan Natives), Asian/Pacific
Islanders, Blacks, Hispanics).  The rationale for studies on single
minority population groups should be provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.
 
The usual NIH policies concerning research on human subjects also apply.
Basic research or clinical studies in which human tissues cannot be
identified or linked to individuals are excluded.  However, every effort
should be made to include human tissues from women and racial/ethnic
minorities when it is important to apply the results of the study
broadly, and this should be addressed by applicants.
 
For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.
 
If the required information is not contained within the application, the
application will be returned.
 
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.
 
All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants or
cooperative agreements that do not comply with these policies.
 
EXCLUSIONS
 
Epidemiological studies and large-scale clinical trials are specifically
excluded from this RFA.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the program project (PO1)
grant.  Although the financial plans for fiscal year 1992 include $7.0
million for the total costs of this program, award of grants pursuant to
this RFA is contingent upon receipt of funds for this purpose.  It is
anticipated that up to five grants will be awarded under this program.
Direct costs are limited to $1.0 million per program project grant for
the first year with increments of 4% per year thereafter.  The specific
amount to be funded will, however, depend on the merit and scope of the
applications received and on the availability of funds.  Since a variety
of approaches would represent valid responses to this announcement, it
is anticipated that there will be a range of costs among individual
grants awarded.  If collaborative arrangements involve sub-contracts
with other institutions, the NHLBI Grants Operations Branch should be
consulted regarding procedures to be followed (tel:  301-496-7536).
 
Applications may be submitted by for-profit or nonprofit organizations,
whether public or private, such as universities, colleges, hospitals,
laboratories, units of State or local governments, and eligible agencies
of the Federal Government.  Applications from minority individuals and
women are encouraged.
 
Upon initiation of the program, the NHLBI will sponsor biannual meetings
to encourage an exchange of information among investigators who
participate in this program.  In the preparation of the budget for the
grant application, applicants must REQUEST ADDITIONAL TRAVEL FUNDS for
two 2-day meetings each year to be held in Bethesda, Maryland.
Applicants must also include a statement in their applications
indicating their willingness to participate in such meetings.
 
Applicants, who will plan and execute their own research programs, are
requested to furnish their own estimates of the time required to achieve
the objectives of the proposed research project.  Up to SEVEN YEARS of
support may be requested.  At the end of the official award period,
renewal applications may be submitted for peer review and competition
for support through the regular program project grant program of the
NHLBI.  It is anticipated that support for the present program will
begin in 1992.  Administrative adjustments in project period and/or
amount of support may be required at the time of the award.
 
All current policies and requirements that govern the research grant
programs of the National Institutes of Health will apply to grants
awarded in connection with this RFA.  Awards in connection with this
announcement will be made to domestic institutions only in accordance
with Public Health Service policy governing such awards.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method
 
Upon receipt, applications will be reviewed for their responsiveness to
the objectives of this RFA.  If an application is judged unresponsive,
the applicant will be contacted to withdraw the application.  If the
application submitted in response to this RFA is substantially similar
to a research grant application already submitted to the NIH for review,
but has not yet been reviewed, the applicant will be asked to withdraw
either the pending application or the new one.  Simultaneous submission
of identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
Applications judged to be responsive will be reviewed for scientific and
technical merit by an initial review group that will be convened by the
Division of Extramural Affairs, NHLBI, solely to review these
applications.
 
This initial review will include a preliminary evaluation to determine
scientific merit relative to the other applications received in response
to the RFA (triage); the NIH will withdraw from further consideration
applications judged to be noncompetitive and promptly notify the
Principal Investigator/program director and the official signing for the
applicant organization.  Those applications judged to be competitive
will be further evaluated for scientific/technical merit by the usual
peer review procedures, including, if deemed appropriate, a reverse site
visit at the applicant's expense.
 
Review Criteria
 
The factors to be considered in the evaluation of each application will
be similar to those used in the review of traditional research and
program project grant applications.  The major factors to be considered
in the evaluation of applications will include:
 
o The significance of the proposed program including its potential for
successfully addressing the primary goal of the RFA:  the integrated
transition of vascular biology into vascular medicine research.
 
o The scientific merit of the proposed component projects, including the
originality and feasibility of the approach, the adequacy of the
experimental design, and the relevance to the overall theme of the
program.
 
o The quality and commitment of senior scientific leadership and their
experience and ability to successfully integrate basic, applied, and
clinical research.
 
o The quality and commitment of a qualified cadre of project
investigators and technical staff with the experience, training, and
abilities to successfully direct each project and core unit.
 
o The physical and intellectual resources and environment in which the
participating laboratories will operate and interact, as well as the
supportive nature and commitment of the sponsoring institutions.
 
o The appropriateness of the requested budget for the proposed program.
 
METHOD OF APPLYING
 
Letter of Intent
 
Prospective applicants are asked to submit a one-page letter of intent
that includes identification of any other participating investigators
and institutions, together with a descriptive title.  The National
Heart, Lung, and Blood Institute requests such letters only for the
purpose of providing an indication of the number and scope of
applications to be received and, therefore, usually does not acknowledge
their receipt.  A letter of intent is not binding, and it will not enter
into the review of any application subsequently submitted, nor is it a
necessary requirement for application.  This letter of intent is to be
received no later than July 31, 1991, should be sent to:
 
Dr. Charles Turbyfill
Review Branch/Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
National Institutes of Health
Bethesda, MD  20892
 
Format for Applications
 
Submit applications on form PHS 398 (revised 10/88), the application
form for the traditional research project grant.  This form is available
in the applicant institution's office of sponsored research or business
office.  Use the format described in the publication entitled:  NHLBI
Program Project Grant - Preparation of the Application, that may be
obtained from the appropriate program administrator listed under
Inquiries.
 
To identify the application as a response to this RFA, CHECK "YES" on
Item 2 of page 1 of the application and enter the title "Program
Projects in Vascular Biology and Medicine" RFA number HL-91-07.
 
THE RFA LABEL ENCLOSED WITH THE PHS-398 FORM MUST BE AFFIXED TO THE
BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION.  FAILURE
TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING AND REVIEW OF YOUR
APPLICATION.
 
Application Procedure
 
Send or deliver the completed application and four signed, exact
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:
 
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD  20892**
 
SEND AN ADDITIONAL TWO (2) COPIES OF THE APPLICATION TO DR.  CHARLES L.
TURBYFILL AT THE ADDRESS LISTED UNDER LETTER OF INTENT.  IT IS IMPORTANT
TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR
COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS.  OTHERWISE THE NHLBI
CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION
FOR THIS RFA.
 
Applications must be received by October 15, 1991.  An application not
received by this date will be considered ineligible.
 
Timetable
 
Letter of Intent                      July 31, 1991
 
Application Receipt Date           October 15, 1991
 
Review by the National Heart, Lung
  and Blood Advisory Council        May 14-15, 1992
 
Anticipated Award Date               August 1, 1992
 
Inquiries
 
Inquiries regarding this request for applications may be directed to the
appropriate program administrator:
 
Dr. David M. Robinson
Associate Director for Scientific Programs
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 416
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-5656
FAX:  (301) 496-9882
Bitnet:  DRW@NIHCU
 
Dr. Carol H. Letendre
Associate Director for Scientific Programs
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 516
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-8966
FAX:  (301) 402-1622
 
Dr. Carol E. Vreim
Associate Director for Scientific Program Operation
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A16C
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-7208
FAX:  (301) 496-9886
 
For fiscal and administrative matters, contact:
 
Marie A. Willett
Chief, Heart and Vascular Grants Management Section
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11C
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-7255
 
This program is described in the Catalog of Federal Domestic Assistance
number 93.837, Heart and Vascular Diseases.  Awards will be made under
the authority of the Public Health Service Act, Section 301 (42 USC 241)
and administered under PHS grant policies and Federal regulations, most
specifically 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive Order
12372, or to Health Systems Agency review.