Subject: NIH GUIDE - Vol. 20, No. 10, March 8, 1991 - RFA DK9108
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 08 Mar 91 10:08 EST

Hi Paul,
   #l2  Please post to the listserver as: RFADK-91-08.910308
          Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA DK9108 DK-91-08 P1O1 *****************************************
 
REQUEST FOR RESEARCH GRANTS APPLICATIONS
 
RFA:  DK-91-08
 
P.T. 34; K.W. 0785095, 0755030, 0765033
 
STUDIES ON THE ETIOLOGY AND PATHOGENESIS OF
POLYCYSTIC KIDNEY DISEASE
 
National Institute of Diabetes and Digestive and Kidney Diseases
 
Letter of Intent Receipt Date:  April 17, 1991
Application Receipt Date:  May 15, 1991
 
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) through the Division of Kidney, Urologic
and Hematologic Diseases (DKUHD), invites research grant
applications directed at defining and further characterizing
the etiology and pathogenesis of Polycystic Kidney Disease
(PKD).
 
BACKGROUND
 
Polycystic Kidney Disease is the most common genetic
disease, affecting 500,000 Americans, with 7,000 new patients
recognized each year.  Since 1982, the number of newly-
diagnosed patients has risen steadily, with a compound
annual rate of 5.7 percent.  Each child of an affected
parent has a fifty percent chance of inheriting the gene.
Two major types of PKD are recognized, autosomal dominant
PKD and autosomal recessive PKD.
 
Polycystic Kidney Disease ranks first among the inherited
and congenital conditions leading to end-stage renal disease
(ESRD); it ranks fourth as a primary cause of ESRD and as a
basic diagnosis among newly identified ESRD patients.  Males
and females are affected equally, and its worldwide
distribution appears to demonstrate that it affects all
races.
 
Although PKD was long considered to be primarily an adult
disease, it also has been found to be a common cause of
cystic disease in children, and thus must be considered in
the differential diagnosis of the pediatric patient.  The
most common form of PKD in humans, autosomal dominant PKD
(ADPKD), has nearly complete penetrance, but variable
expression.  About 25 percent of patients are unable to give
a family history consistent with ADPKD, suggesting the
possibility of a high rate of spontaneous mutations in the
"PKD locus".  An alternative possibility is that
environmental or other factors may have a strong effect on
the expression of ADPKD.
 
A less frequent form of PKD in humans, autosomal recessive
PKD (ARPKD), is inherited as an autosomal recessive trait.
ARPKD is rarely recognized in parents of affected children,
occurring once in 6,000 to 14,000 live births.  Patients
with less severe forms of the disease who survive the
newborn period often develop renal insufficiency at some
point during the course of the disease.
 
A newly recognized type of PKD, acquired PKD (ACPKD),
develops in kidneys injured by a variety of chronic renal
disorders, and leads to progressive renal insufficiency.  It
also develops in long-term hemodialysis patients.  This form
of PKD has been associated with a high incidence of
malignant transformation.
 
A major advance in understanding PKD etiology was made in
1985.  Using gene linkage techniques, a gene for ADPKD was
localized to the short arm of chromosome 16.  Although the gene
itself was not found, DNA markers near the gene were
identified.  In 1988, an affected family was discovered in
which the PKD gene was found in a location other than
chromosome 16.  That this was not a unique finding was
confirmed by the subsequent finding of similarly affected
families.  The first gene, located on chromosome 16, has
been called ADPKD1.  The other gene(s) not yet localized,
has been called ADPKD2 or non-ADPKD1, to convey the
possibility that there may be even more than two ADPKD genes
or loci.  While ADPKD1 appears to account for 90 percent of all
ADPKD in the Caucasian population, the distribution between
the genotypes for other racial groups remains to be
determined.  The significance of the apparent correlation of
the chromosomal localization with the time of onset of the
disease needs to be examined.
 
Thus, ADPKD, which appeared clinically to be one disease,
actually may result from different genetic defects.  Because
the gene products are likely to be different, it is
reasonable to expect that the clinical manifestations also
will be different.
 
Because the pathogenesis of PKD remains undefined, it is not
possible to develop rational approaches to prevention and
treatment.  The nature of the biochemical defect, which
leads to cyst formation and consequent cyst growth, and the
relationship between the extent of cyst formation and the
development of progressive renal insufficiency are not
understood.  There are proponents of the idea that the renal
cyst may be one of a limited repertoire of responses of the
kidney to tubular epithelial injury, and that injurious
agents act in a limited number of pathways.  However, there
is increasing evidence that the primary abnormality is one
of disordered cell growth whereby cyst formation and growth
are controlled by the combined action of growth-promoting
factors.  Some evidence suggests that epidermal growth
factor may initiate cyst formation, and that cyclic AMP
accelerates cyst formation and expansion.
 
PKD presents in a variety of clinical forms, often with a
slow progressive course to renal insufficiency.  Thus,
different avenues of research should be pursued in order to
gain a better understanding of the genetic factors leading
to PKD, the pathogenetic mechanisms leading to cyst
formation and growth, the diversity in clinical expression,
and the identification of effective treatment to prevent or
control this major problem.
 
OBJECTIVES AND SCOPE
 
The purpose of this Request for Applications is to stimulate
high quality research efforts to further the understanding
of the etiology and pathogenesis of PKD.  Examples of areas
for investigation include:
 
Isolation, sequencing and cloning of the ADPKD1 gene(s);
gene regulation studies; identification of linkage markers
to define chromosomal location for the non-ADPKD1 gene(s)
and for the ARPKD gene; examination of the heterogeneity of
ARPKD; and characterization of gene mutations.
 
Identification of key cellular and molecular pathogenetic
factors leading to cyst formation and growth, including
processes and factors resulting in epithelial proliferation,
fluid accumulation, and regulation of extracellular matrix
formation.
 
Development of in vitro models of renal cyst formation using
cell lines or isolates, such as those obtained by the
transfection with various types of genetic material or
immortalization of cells from affected persons.
 
Applications proposing clinical trials are not requested at
this time.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the
traditional, individual, investigator-initiated Research
Grant (RO1) Application, and it is governed by the policies
applicable to such awards.  Approximately $1.2 million in
total direct and indirect costs are anticipated to be
available to fund applications submitted in response to this
RFA.  However, the funding of such applications is
contingent on the actual availability of funds, and the
receipt of applications of sufficient scientific merit.  It
is anticipated that five to seven awards will be made, for
an average of 4 years per award.  The specific amounts
to be awarded will depend on the merit and scope of the
applications received.  Furthermore, because diverse
approaches may represent valid responses to this
announcement, it is anticipated that there will be a range
of costs among individual awards.  Awards may be made to
foreign institutions for research of unusual merit and
promise, in accordance with PHS policy governing such
awards.  It is anticipated that support for successful
applications will begin on September 30, 1991.
 
Upon initiation of the program, the NIDDK will sponsor
periodic meetings to encourage exchange of information among
participating investigators, and with other investigators
with related interests.  Therefore, the application budgets
must request travel funds for a two-day meeting each year,
most likely to be held in Bethesda, Maryland.  The
application budget section also must include a statement
indicating willingness of the applicant to participate in
such meetings.
 
The current policies and requirements that govern the
review, funding, and performance of research grant programs
of the NIH will prevail.
 
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.
 
APPLICATIONS AND REVIEW PROCEDURES
 
Upon receipt, applications will be reviewed by the Division
of Research Grants (DRG) for completeness.  Incomplete
applications will be returned to the applicant without
further consideration.  Applications also will be evaluated
for responsiveness to the RFA.  Those judged non-responsive
will be returned to the applicant but may be submitted
as investigator-initiated regular research grants at the
regular receipt dates.  Questions concerning the
responsiveness of proposed research to the RFA should be
directed to Program staff (see the final page of this below).
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.
 
In cases where the number of applications is large compared
to the number of anticipated awards, the NIH may conduct a
preliminary scientific peer review to eliminate those
applications which clearly are not competitive.  The NIH
will withdraw administratively from competition those
submissions judged to be noncompetitive, and will notify the
applicant and the institutional business official.
 
Those applications judged to be both competitive and
responsive will be reviewed for scientific and technical
merit by an Initial Review Group convened by the Division
of Extramural Activities, NIDDK, solely to review these
applications.  Review criteria include: extent of relevance
and/or contribution of the proposed research to the overall
goals and objectives of the RFA; significance and
originality of research goals and approaches; feasibility of
the research and adequacy of the experimental design;
experience and research competence of the investigator(s);
adequacy of available facilities; inclusion of women and
minorities (when applicable) or a clear rationale provided
for their exclusion; appropriate consent forms for patient
participation (when applicable); provision for the humane
care of animals (when applicable); and appropriateness of
the requested budget relative to the work proposed.
 
Funding decisions will be based on scientific merit, program
relevance, and availability of funds, and on recommendations
by the Initial Review Group and the National Diabetes and
Digestive and Kidney Diseases Advisory Council.
 
METHOD OF APPLYING
 
LETTER OF INTENT:  Prospective applicants are asked to
submit a letter of intent that includes a
descriptive title of the grant application, the name of
the Principal Investigator, and any participating
institutions.  Such letters are requested in order to
determine the number and scope of applications likely to be
received.  Their receipt will not be acknowledged.  A letter
of intent is not binding and will not enter into the review
of any application submitted subsequently, nor is it
required for application.  This letter of intent, which
should be received by April 17, 1991, must be sent to:
 
Robert D. Hammond, Ph.D.
Chief, Review Branch, DEA
National Institute of Diabetes
and Digestive and Kidney Diseases
National Institutes of Health
Westwood Building, Room 406
Bethesda, MD  20892
 
Applications must be submitted on form PHS 398 (revised
10/88) available in the Business or Research Grants Offices
of most academic or research institutions, and from the
Office of Grants Inquiries, Division of Research Grants,
Room 449, Westwood Building, 5333 Westbard Avenue, National
Institutes of Health, Bethesda, Maryland, 20892.
Applications will be accepted until close of business on
May 15, 1991.  No extensions will be granted on the
application deadline.
 
The phrase "RFA DK-91-08:  Studies on the
Etiology and Pathogenesis Polycystic Kidney
Disease" must be typed on line 2 of the face page of form
PHS 398.  Applicants should request a start date of
September 30, 1991.
 
THE RFA LABEL (AVAILABLE IN THE 10/88 REVISION OF
APPLICATION FORM 398) MUST BE AFFIXED TO THE BOTTOM OF THE
FACE PAGE OF THE ORIGINAL COPY OF THE APPLICATION.  FAILURE
TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF THE
APPLICATION.
 
The completed original application and four (4) signed,
exact photocopies should be sent or delivered to:
 
Grants Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
Two additional copies of the application should be sent to:
 
Robert D. Hammond, Ph.D.
Chief, Review Branch, DEA
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 406
Bethesda, MD  20892
 
IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME
THAT THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION
OF RESEARCH GRANTS.  IF THESE ARE NOT SENT IT CANNOT BE
GUARANTEED THAT THE APPLICATION WILL BE REVIEWED IN
COMPETITION FOR THIS RFA PROGRAM.
 
TIME TABLE
 
Letter of Intent                    April 17, 1991
Application Receipt Date            May 15, 1991
Review by Council                   September 12-13, 1991
Anticipated Award Date              September 30, 1991
 
Inquiries regarding this announcement may be directed to:
 
Gladys H. Hirschman, M.D.
Director, Chronic Renal Diseases Program
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Federal Building, Room 102
Bethesda, MD  20892
Telephone:  (301) 496-8218
 
For fiscal and administrative matters, contact:
 
Ms. Donna Huggins
Grants Management Specialist
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 653
Bethesda, MD  20892
Telephone:  (301) 496-7467
 
These programs are described in the catalog of Federal
Domestic Assistance No. 93.849 - Kidney, Urologic and
Hematologic Diseases Research - and awards will be made
under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-
4110, 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 subjected to the
intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.