NIH Guide, Volume 26, Number 35, October 17, 1997

PA NUMBER:  PAS-98-002

National Institute of Diabetes and Digestive and Kidney Diseases


The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) through its Division of Kidney, Urologic and
Hematologic Diseases (DKUHD) invites experienced and new
investigators to submit research grant applications to pursue basic
and applied investigations in order to better understand the
etiology and pathogenesis of Polycystic Kidney Disease (PKD), both
dominant and recessive; the genetic determinants, and cellular and
molecular mechanisms which disrupt normal kidney function;
mechanisms of cyst formation and growth; development of
experimental model systems; development of imaging methods to
assess cyst growth and provide markers of disease progression; and
the identification of innovative therapeutic interventions and gene
targeted strategies to prevent progressive renal insufficiency due
to this disorder.  The intent of the Program Announcement (PA) is
to intensify investigator-initiated research, to attract new
investigators to the field, and to increase interdisciplinary
research.  The ultimate aim is to encourage and facilitate PKD-
related research studies where progress already attained offers new
opportunities to increase the pace with which knowledge is accrued.


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 PA, Polycystic Kidney Disease (PKD): Mechanisms, Model
Systems, Interventions, 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
Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).


Applications may be submitted by domestic and foreign, for-profit
and non-profit organizations and institutions, public and private,
such as universities, colleges and laboratories, units of State and
local governments, and eligible agencies of the Federal government. 
Foreign institutions are not eligible for First Independent
Research Support and Transition (FIRST) (R29) awards. 
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.


Support of this program will be through the National Institutes of
Health (NIH) research project grants (R01), Interactive Research
Project Grants (IRPG) and FIRST award (R29) support mechanisms. 
FIRST (R29) award applications must adhere to the FIRST (R29)
administrative guidelines for eligibility, budget, and period of
award.  Potential applicants contemplating the submission of an
IRPG should contact the program official listed under "INQUIRIES"
at an early opportunity.  Guidelines for preparing IRPG
applications are available from the program official or from the
internet at: http://grants.nih.gov/grants/guide/

Applications from institutions that have a General Clinical
Research Center (GCRC) funded by the NIH National Center for
Research Resources may wish to identify the GCRC as a resource for
conducting the proposed research.  If so, a letter of agreement
from either the GCRC program director or principal investigator
should be included with the application.


A total of $ 2.5 million will be committed by the NIDDK in FY 1998
and FY 1999 to fund applications of high scientific merit submitted
in response to this Program Announcement.  It is anticipated that
a total of 10-12 applications will be funded during the two fiscal
years. In general, the maximum budget request should be limited to
$160,000 in direct costs for the initial budget period.  Requests
for support that exceeds that amount will require a thorough
justification, and in no case will a request exceeding $250,000
direct cost for the initial budget period be allowed under this
solicitation. Although this program is provided for in the
financial plans of the NIDDK, the award of grants pursuant to this
PA is also contingent upon the availability of funds for this



Polycystic Kidney Disease is a serious and costly disease.  About
500,000 people in the USA are estimated to have PKD, and it is the
third leading cause of end-stage renal failure in the nation.  The
important advances in understanding the molecular basis of adult
dominant PKD (ADPKD1 and ADPKD2) have generated intense interest
and have provided investigators with important research
opportunities.  Although certain topics are already receiving
careful study, the timely opportunities to discover more about the
etiology and pathogenesis of PKD in particular, and the related
cellular and molecular mechanisms that determine kidney function in
general, need to be addressed.  These investigations, largely
fundamental, are likely to generate, in the foreseeable future, a
variety of possible strategies for clinical intervention.  The
focus of this research initiative is investment in the groundwork
that will facilitate the eventual testing of such strategies. 
Substantial difficulties exist in the translation of fundamental
insight into therapeutic methods, including the slow rate of
progression of the disease in patients and the difficulty of
monitoring cyst growth.  The development of experimental models
which mimic human disease is an important goal.  Also critical will
be the development of improved methods to monitor progression of
disease in patients.  Development of imaging methods which assess
cyst growth and provide markers of disease progression could
markedly improve the feasibility of clinical trials.  Another
important area of investigation is the identification of genetic
modifiers of human ADPKD to elucidate the interactions between PKD-
susceptibility loci and their genetic modifiers.

Research Goals and Scope

It is the intent of this solicitation to invite applications from
investigators with diverse scientific interests, who wish to apply
their expertise into basic and applied research to enhance the
understanding of the etiology and pathogenesis of PKD, both
dominant (ADPKD) and recessive (ARPKD); the genetic determinants
and cellular and molecular mechanisms which disrupt normal kidney
function; the mechanisms of cyst formation and growth at the
cellular and molecular levels; the development of experimental
model systems; the development of imaging methods to assess cyst
growth and disease progression; and research studies aimed at the
identification of therapeutic opportunities and gene targeted
strategies to prevent progressive renal insufficiency due to this

Examples that illustrate areas to be considered within the intent
of this solicitation are presented in the following paragraphs. 
These examples are meant only to provide a broad direction and
should be considered illustrative, and not restrictive.  Examples,
include the following:

1. Clinical Aspects of PKD

-  Studies to enhance the understanding of the phenotype/genotype
correlation and disease phenotypes in different genetic
backgrounds, i.e., gender, race, and ethnicity.

-  Risk factors for poor clinical outcome, i.e., hypertension, role
of post-menopausal estrogens, mechanisms and interventions for
hypertension and cardiovascular complications, chronic abdominal
pain and flank pain, etc., in PKD.

-  Studies of the role of genes in determining severity of disease
and extra-renal manifestations and predicted impact of mutations on

-  Studies addressing the possible role of PKD-related phenotypes
and somatic mutations with or without germline mutations in people
with and without PKD and significance of these mutations.

-  Identification of surrogate markers of disease progression in
PKD that could be used to monitor the course of the disorder from
its early stages.

-  Studies focusing on disease manifestation and management in
children with PKD.

-  Assembling of cohorts of well characterized ADPKD and ARPKD
patients suitable for future studies of therapeutic modalities.

-  Development of imaging and other improved methods to assess cyst
growth and provide markers of disease progression, to improve the
feasibility of clinical trials.

-  Identification of innovative therapeutic interventions and gene
targeted strategies to prevent renal disease progression in this

2. Genetic Aspects, Structure and Function

The overall goal is to identify and characterize genes involved in
cystogenesis, to elucidate their interactions with one another, and
to define the molecular pathway(s) in which they operate.

-  Identification and study of PKD genes, their structure and

-  Identification and characterization of additional PKD genes and
genes for the unlinked form(s) of ADPKD, ARPKD, and infantile
cystic disease.

-  Characterization of the expression pattern of ADPKD1 and ADPKD2,
mRNA and proteins, and functional analysis of their gene products
and interacting proteins.

-  Studies focusing on the function of individual domains, domain-
domain interaction between PKD1 and PKD2; their function , i.e.,
ligand-receptor complex, production of dominant/negative mutants,

-  Identification of mammalian homologs corresponding to genes
causing cysts in lower species.

-  Development of improved strategies for mutation detection.

-  Characterization of mutations (pathogenic and non-pathogenic),
and definition of mechanisms from mutation to phenotype, i.e., how
mutation leads to disease.

-  Studies to identify and describe the role of genetic modifiers
of human PKD.

-  Development of strategies for dissecting out PKD signaling

-  Development of biochemically-based functional assays that can be
utilized to dissect polycystin protein-protein interaction.

-  Studies to isolate and characterize protein(s ) involved in the
signal transduction pathway in PKD; studies to address issues
concerning cell-cell communication, signaling, and cell-matrix

-  Investigation of experimental gene sequence modification, and
identification of pathways and pathways modifiers.

-  Development of tools for genetically accurate model systems for

3. Disease Pathogenesis

A coordinated approach integrating molecular genetics, cell biology
and structural biology of PKD is seen as imperative to the
understanding of the mechanistic details in the pathogenesis of
this disease.

-  Studies directed at defining the role of the PKD1 and PKD2 gene
structure in the molecular pathogenesis of PKD.

-  Studies addressing the role of polycystin-1, polycystin-2, and
their ligands and associated proteins in normal and abnormal kidney

-  Studies focusing on the role and interaction of the polycystins
with other important genes in kidney development.

-  Studies addressing the pathogenesis of PKD through the
development of experimental systems including cell culture from
existing models of rapidly as well as slowly progressive PKD.

-  Studies with a multi-faceted approach, integrating renal
morphogenesis (induction, epithelial-mesenchymal interactions,
branching, pattern formation, etc.,) and PKD.

-  Studies aimed at generating critical information concerning
epithelial cell differentiation, cell adhesion, signaling,
communication, etc., in the developing kidney and in the
pathogenesis of PKD.

-  Identification of novel regulators of kidney morphogenesis
including growth factors, extracellular matrix components, cell
adhesion molecules, and transcriptional regulatory proteins.

-  Studies utilizing molecular genetic approaches to address the
role of growth factors and components of their pathway in the
pathogenesis of PKD and studies on the role of inflammation and
interstitial fibrosis, control of cell growth and differentiation,
etc, in the pathogenesis of PKD.

-  Studies focusing on polarity, role of signaling molecules, role
of PKD1 and PKD2 on polarity.

-  Studies addressing the possible role of the polycystins in
signal transduction and characterization of the components of such

-  Studies addressing the localization of PKD1 and PKD2,
developmental profile, and role in renal injury.

-  Studies addressing the pathogenesis of cyst formation, transport
pathways involved, role of PKD genes in inhibiting cystogenesis, or
in regulating renal tubule formation.

-  Studies exploring the role of apoptosis on progression of PKD.

-  Studies addressing the possible role of DNA conformational
features in the etiology and pathogenesis of PKD.

4. Experimental Model Systems

-  Development and characterization of experimental model systems
faithful to PKD human disease, to aid in the understanding of its

-  Development of mouse transgenic lines with targeted disruption
of PKD genes or their signaling molecules to ascertain the role of
the genetic background on disease expression.

- Identification of genes in non-mammalian species i.e. the
Zebrafish as a potential cystic model, where studies of the renal
development could be considered as well as cloning of PKD
homologues in the Zebrafish could be attempted.

-  Studies exploring the phenotypic consequences of PKD1 and PKD2
mutations in kidney and liver cell lines.

-  Development of immortalized cell lines from human kidney and
liver for ADPKD1 and 2 and ARPKD.

-  Identification of PKD-susceptibility genes; identification and
mapping modifying genes to learn about their role as modifying loci
for one another; elucidation of interactions between PKD-
susceptibility loci and their genetic modifiers.

-  Studies applying functional genomic strategies to complement the
current positional cloning efforts to identify the different PKD
mutations in the mouse model.

-  Furthering research efforts on the mutagenesis of the entire
mouse genome; identification of new mouse PKD mutant genes and new
alleles of known genes; and characterization of such expanded
mutant resource at both genetic and phenotypic level.

-  Formulation of strategies aimed at developing mutant alleles in
known PKD genes, and conduct studies designed to evaluate
phenotype-genotype correlation at a molecular and at a functional

-  Development of megabase delition strategies and resources which
could be used, i.e., to replace the PKD1 gene with its human
homolog to provide an in-vivo model for the study of mutagenesis of
the PKD1 gene, and other applications.

5. Therapeutic Approaches:

-  Evaluation of the efficacy of therapeutic interventions in
attenuating specific secondary processes including the reversal of

-  Identification of methods to block cyst formation.

-  Development of in-vivo vectors which provide high efficiency
delivery to renal tubular cells, interstitium, or vasculature in a
model of PKD (i.e., "renotropic" vectors).

-  Development of in-vivo vectors (e.g., novel packaging lines)
which allow for long-term expression or repeated therapy as a way
of getting chronic expression, in preparation for gene therapy in

-  Testing of gene replacement therapy, testing of genes with anti-
inflammatory, anti-fibrotic, or anti-proliferative activities,
etc., in models of PKD.


It is the policy of the NIH that women and members of minority
groups and their sub-populations 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 policy results from the NIH Revitalization Act of
1993 (Section 492B of Public Law 103-43).

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 in the NIH Guide for Grants and Contracts, Volume
23, Number 11, March 18, 1994.

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.


Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits
are available at most institutional offices of sponsored research,
or may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-435-0714, email: asknih@od.nih.gov.

The program announcement title and number must be typed on line 2
of the face page of the application form and the YES box must be

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 applications submitted without
the required number of reference letters will be considered
incomplete and will be returned without review.

Submit the signed, original, single-sided application, along with
five exact, single-sided copies and five collated sets of appendix
materials to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with NIH peer
review procedures. As part of the initial merit review, all
applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under
review, will be discussed, assigned a priority score, and receive
a second level review by the appropriate national advisory council
or board.

Review Criteria

o  Significance:  Does this study address an important problem?  If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?

o  Approach:  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?

o  Innovation:  Does the project employ novel concepts, approaches
or method? Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or

o  Investigator:  Is the investigator appropriately trained and
well suited to carry out this work?  Is the work proposed
appropriate to the experience level of the principal investigator
and other researchers (if any)?

o  Environment:  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements? 
Is there evidence of institutional support?

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 evaluated.

The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.

o  Availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations,
or environmental conditions in other countries which are not
readily available in the United States or which provide
augmentation of existing U.S. resources.


Applications will compete for available funds with all other
approved applications.  The following will be considered in making
funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority.


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

Inquiries regarding programmatic issues may be directed to:

Gladys H. Hirschman, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  gladys_hirschman@nih.gov

Inquiries regarding fiscal and administrative matters may be
directed to:

Aretina D. Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
FAX:  (301) 480-3504


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 review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children. This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.

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