Full Text DK-95-002


NIH GUIDE, Volume 23, Number 38, October 28, 1994

RFA:  DK-95-002

P.T. 34

  Biology, Cellular 
  Biology, Molecular 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 28, 1995
Application Receipt Date:  May 23, 1995


The Division of Kidney, Urologic and Hematologic Diseases (DKUHD),
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research project grant
applications and Interactive Research Project Grants (IRPG), to
encourage and facilitate studies designed to develop promising basic
cellular, molecular, biochemical, physiological, and genetic
approaches to autosomal dominant and recessive renal cystic diseases.


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 Request
for Applications (RFA), Basic Studies of Renal Cystic Disease, is
related to the priority area of chronic disabling diseases.
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).


Applications may be submitted by domestic and foreign, for-profit and
not for-profit organizations and institutions, public and private,
such as universities, colleges, hospitals, laboratories, units of
State and local governments, and eligible agencies of the Federal
Government.  Applications may be submitted by single institutions and
by a consortia of institutions.  Foreign institutions are not
eligible for First Independent Research Support and Transition
(FIRST) (R29) awards.  Applications from racial/ethnic minority
individuals, women, and persons with disabilities are encouraged.


This RFA will use the National Institutes of Health (NIH) research
project grants (R01s), Interactive Research Project Grants (IRPG) and
FIRST (R29) award support mechanisms.  FIRST award applications must
adhere to the R29 administrative guidelines (rev. 9/93) for
eligibility, budget, and period of award.

Responsibility for planning, direction, and execution of the proposed
project will be solely that of the applicant.  Because the nature and
scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of an award will vary also; however,
requests must not exceed the NIDDK average grant size of $160,000
direct costs for the initial budget period for both R01s and IRPGs.
The lead IRPG, however, may include a request for up to an additional
$50,000 direct costs for shared resources (SPECIAL INSTRUCTIONS FOR
requested from the Program Official listed under INQUIRIES).  The
total requested project period for R01 and IRPG applications
submitted in response to the present RFA may not exceed five years.
FIRST awards must be for five years and the total direct cost award
for the five-year period may not exceed $350,000.  The anticipated
award date is September 30, 1995.

This RFA is a one-time solicitation for fiscal year 1995.  However,
the NIDDK may reissue the RFA in future years.  In anticipation that
there will be a continuing program need, the NIDDK will encourage
recipients of awards under this RFA to submit competing continuation
applications that will be reviewed according to the customary peer
review procedures.


For FY 1995 $2.5 million in total costs per year, plus standard
incremental increases for five years, will be committed by the NIDDK
to fund applications submitted in response to this RFA.  It is
anticipated that 12 to 15 awards will be made.  Although this program
is provided for in the financial plans of the NIDDK, the award of
grants, as well as the final amounts awarded, will be contingent upon
the availability of funds for this purpose.



Adult autosomal dominant polycystic kidney disease (ADPKD) is the
most common hereditary renal disease in the United States, affecting
an estimated 1 in 500 to 1 in 1,000 people.  Best estimates indicate
that there are 600,000 ADPKD patients in the United States and that
it accounts for 9 to 11 percent of all end-stage renal failure in
this country; however, many ADPKD patients never reach end-stage
renal failure and many reach end-stage only late in life.  Studies
indicate that progression of renal disease to end-stage in ADPKD is
influenced by many factors in addition to the culprit gene,
including: gender, race, age at diagnosis, hypertension, increased
left ventricular mass, gross hematuria, mean renal volume, urinary
tract infections (males), hepatic cysts (females) and three or more
pregnancies (females).  Currently, there is considerable interest in
identifying intervention(s) that may slow down or arrest the
progression of ADPKD.  Among 200 ADPKD patients who participated in
the recently reported Modification of Diet in Renal Disease Study,
there was no substantial benefit of either a lower than usual blood
pressure goal (e.g., <140/90 mmHg) or a low or very low protein diet
on disease progression (rate of GFR decline) in patients with
advanced disease.

Supporting evidence indicates that renal cyst growth involves at
least four primary pathogenetic mechanisms:

1.  Abnormal Regulation of Epithelial Cell Growth, Resulting in
Increases in Surface Area of Renal Tubules.  Renal cysts are
comprised of epithelial cells derived from progenitor renal tubules.
These cells exhibit increased rates of proliferation, proto-oncogene
expression and appear to be de-differentiated in respect to the
tubule segment of origin.

2.  Abnormal Transport by Epithelial Cells, Resulting in the
Accumulation Within the Cyst Cavity of Fluid Derived from Glomerular
Filtrate and Transepithelial Secretion.  The fluid in renal cysts
derives primarily from the transepithelial secretion of NaCl and
water.  This abnormality may be secondary to abnormal Cl- transport
or Na+ secretion.

3.  Remodeling of the Extracellular Matrix Surrounding Cysts.  The
extracellular matrix is abnormal in cystic kidneys.  In the dominant
form of the disease in humans, aneurysms, hernias, colon diverticuli,
and floppy mitral valves suggest a connective tissue abnormality.

4.  Gene Etiology of Hereditary Polycystic Kidney Disorders: Progress
in Cloning.  The cause of PKD is known in several disease states.
The dominantly inherited disease, PKD1 has recently been shown to map
to 16p13.3.  The chromosome translocation associated with ADPKD that
disrupts a gene (PBP) encoding a 14 kb transcript has been identified
in the PKD1 candidate region.  Further mutations of the PBP gene were
found in PKD1 patients, two deletions (one a de novo event) and a
splicing defect, confirming that PBP is the PKD1 gene.  The recessive
form, which affects primarily children, has not been defined.
Medullary cystic disease has been recently assigned a 2P chromosomal

The identification of the PKD1 gene is a major step toward
understanding the molecular pathology of this complex disorder.
Information currently available should allow study of the PKD1
protein to determine both its normal role in the cell and the
mechanism by which mutation of the PKD1 gene cause the major renal
cystic disease in humans.  Progress in preventing and treating this
disease will be enhanced when fundamental understandings of
pathogenesis are achieved.  The cross-fertilization of the
disciplines of genetics and molecular biology, cell chemistry and
biology, immunology, physiology, microbiology, and pathology have
resulted in new and extremely useful experimental tools that allow
researchers to address and seek answers to questions at a fundamental
level.  The regulation of cellular growth continues to be an area of
intense investigation in kidney research and investigators have
identified several growth factors and determined their exact chemical
composition.  The powerful tools of molecular biology (i.e.,
polymerase chain reaction and in situ hybridization techniques) offer
further promise for expanding our knowledge about the regulatory
genes that control differentiation and encode the signals that
establish the precise topographical patterns essential to the
function of the fully developed kidney.  Fostering further research
at the molecular level to address cellular and basic mechanisms,
beginning with the developing kidney, may raise the possibility of
new breakthroughs that will lead to effective treatment of ADPKD
and/or its prevention.

Research Goals and Scope

This special grant program will support fundamental basic research,
with an emphasis however, to foster extensive collaboration between
individuals in the basic sciences, including biochemistry, cell
biology, embryology, endocrinology, molecular biology, genetics,
nutrition, pathology, pharmacology, renal physiology and in
pathophysiology.  It is the intent of this solicitation to engage
investigators with diverse research interests who wish to apply their
technologies and expertise in elucidating and extending the current
understanding of the genetic aspects of autosomal dominant and
recessive renal cystic diseases and the cellular and integrated
mechanisms in the developing kidney.

Some examples of renal cystic disease research directions in which
applications would be considered responsive to this RFA include, but
are not limited to:

o  Genes and gene products with critical roles in cystic kidney
development and differentiation;

o  Expression of the protein(s) from the cDNA;

o  Studies of expression of ADPKD locus protein(s) during development
and disease progression;

o  Definition of the mutations that cause polycystic kidney disease
(autosomal dominant and recessive);

o  Mechanisms of action of growth factors and protooncogenes,
cytokines, and other regulators of kidney growth and development in
cystic kidneys;

o  Influence of extracellular matrix composition and architecture on
kidney basement membrane in renal cystic disease;

o  Mechanisms underlying the involvement of specific ion, solute and
water transporter(s) in ADPKD; development of inhibitors of solute
and fluid secretion in ADPKD cysts;

o  Application of current knowledge of pathobiology of renal cystic
disease to treatment in animal models;

o  Development of animals transgenic for renal cystic diseases
(autosomal dominant and recessive), including the identification of
modifier genes;

o  Development of cell lines for study of renal cystic disease.

Investigators are not limited to the above examples of research
areas, and are encouraged to propose other approaches that are
appropriate to the investigator-initiated R01, Interactive Research
Project Grant and FIRST (R29) mechanisms and the requirements of this


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

For applications containing foreign collaboration components, 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.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Prospective applicants are encouraged to submit an optional letter of
intent by March 28, 1995.  Included should be the descriptive title
of the proposed research, the name, address, and telephone number of
the Principal Investigator, the identities of other key personnel and
all participating institutions, and the number and title of the RFA
in response to which the application may be submitted.  Although a
letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information allows
NIDDK staff to estimate the potential review workload and avoid
conflict of interest in the review.

The letter of intent is to be sent to:

Robert D. Hammond, Ph.D.
Division of Extramural Program Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Bethesda, MD  20892-6600


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267; and from the program administrator listed

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in the delayed processing of
the application such that it may not reach the review committee in
time for review.  In order to assure proper identification of the
application, line 2a of the application form must state "DK-95-002,
Basic Studies of Renal Cystic Disease" and check the "YES" box.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must be sent to Dr. Hammond at the address listed under LETTER OF

Applications must be received by COB May 23, 1995 and no unsolicited
material will be accepted after the official receipt date.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The DRG will not
accept any application that is essentially the same as one already
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.


Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NIDDK. Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIDDK staff will contact
the applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
grant applications during the next review cycle.

As part of the initial merit review, a process (triage) may be used
by an initial review group convened by the NIDDK in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the institutional official signing for the
applicant organization will be notified.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIDDK in July 1995 in accordance with
review criteria stated below and Advisory Council review September
1995.  The earliest requested begin-date should be September 30,

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research specific to the objectives of the RFA;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be


Funding decisions will be based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.


Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Gladys H. Hirschman, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes, Digestive and Kidney Diseases 45
Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7522
FAX:  (301) 594-7501

M. James Scherbenske, Ph.D
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes, Digestive and Kidney Diseases 45
Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7522
FAX:  (301) 594-7501

For fiscal and administrative matters, contact:

Mrs. Aretina Perry
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7543


Letter of Intent Receipt Date:  March 28, 1995
Applications Receipt Date:      May 23, 1995
Initial Review:                 July 1995
Council Review:                 September 1995
Earliest Start Date:            September 30, 1995


This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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