INTERDISCIPLINARY CENTERS FOR POLYCYSTIC KIDNEY DISEASE RESEARCH

Release Date:  January 22, 1999

RFA:  DK-99-012

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 12, 1999
Application Receipt Date:  April 13, 1999

PURPOSE

It is the intent of this Request for Applications (RFA) to expand the basic
research infrastructure in polycystic kidney disease (PKD), both for the
autosomal dominant (ADPKD) and the recessive (ARPKD) forms.  The development of
Center grants has proven to be a valuable way to promote multidisciplinary
interactions and to provide shared resources needed to address complex biomedical
problems, such as therapy of PKD.  Centers can provide the basis for generation
of technologies which can be applied by other investigators and clinicians in
many medical centers throughout the nation.  Therefore, the purpose of the
Interdisciplinary Centers for Polycystic Kidney Disease Research (ICPKD) is to
attract a partnership of interdisciplinary research among investigators with
scientific expertise who will use complementary and integrated approaches.

The proposed studies should foster and extend the development of new approaches
into the causes, early diagnoses, and improved treatments for PKD.  Institutions
with extensive scientific expertise in the areas of cellular and molecular
biology, genetics, protein chemistry, structural biology, immunology, pathology,
physiology, nutrition, epidemiology, clinical trials, and animal model and drug
development are encouraged to apply.  Eligibility for an award is limited to
domestic institutions.

HEALTHY PEOPLE 2000

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 is related to one or more of the
priority areas.  Potential applicants may obtain a copy of "Healthy People 2000"
at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of  State and local governments, and eligible agencies of the
Federal government.  Foreign institutions are not eligible for Center grants,
however, with appropriate justification, collaborations with foreign
investigators are allowed.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as Principal Investigators.

Any domestic institution or consortium wishing to qualify for an ICPKD should
have an active program of excellence in basic and clinical biomedical research,
not necessarily restricted to the kidney but to biological questions in general,
which may have relevance to this initiative. Excellence of the proposal will be
demonstrated by peer reviewed research support, publications in peer-reviewed
journals, as well as substantive contributions to knowledge relevant to the
research proposed within the Center application.

Research projects to be supported by the ICPKD should be directed to the
development of fundamental knowledge leading to understanding of the disease
processes and the design of preventive and/or curative strategies.  Core
facilities should be shared resources that enhance productivity and aid in
accomplishing the stated goals of the Center.  Pilot and feasibility studies may
also be included and independently supported by the ICPKD.  Monetary resources
for such new initiatives or feasibility studies may be for the support of
new/young investigators, or established investigators who are moving into new
areas of research directly related to the central goals of the Center.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Specialized Centers of
Research (P50) award mechanism.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicants.  The
total project period for an application submitted in response to this RFA may not
exceed 5 years.  This RFA is a one-time solicitation and at this time the NIDDK
has not determined whether this solicitation will be continued beyond the present
solicitation; however, at the time the present initiative nears completion a
follow up RFA will likely be issued in 2003.  The anticipated award date for the
successful applicants of the current RFA is September 1999.

FUNDS AVAILABLE

The NIDDK will commit $4.0 million in FY 1999 to fund up to four new Center
grants in response to this RFA.  An applicant may request a project period of up
to five years and an adequately justified  budget for direct costs of up to
$750,000 per year, excluding indirect costs for consortium arrangements.  Non-
competing years will be limited to the NIH-wide escalation factor of 3 percent,
but the total direct cost request cannot exceed the five-year direct cost cap of
$3.75 million.

Although the financial plans of the NIDDK provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and the
receipt of a sufficient number of applications of outstanding scientific and
technical merit.

RESEARCH OBJECTIVES

A.  Background

PKD is the fourth leading cause of end-stage renal disease (ESRD) in America, and
contributes appreciably to the associated health care costs for renal failure in
the ESRD population.  A striking feature of PKD is the variability with which it
affects the patient.  Some develop only a modest number of renal cysts during
their lifetime and may not be aware of being affected by this disorder.  Others
develop a massive number of renal cysts and may reach renal failure at an early
age.  It is not unusual for cysts to develop in the liver and within the systemic
vasculature.  Recent evidence indicates that besides the documented cyst
enlargement and interstitial fibrosis, apoptotic loss of non-cystic nephrons is
a significant component of the pathology of PKD and may contribute to the
progressive loss of renal function.  Despite the salient changes in the
structural aspects of the kidney and the fact that ADPKD is one of the most
common, potentially lethal genetic diseases known, little systematic research on
the cellular mechanisms of the disease was carried out until the past two
decades.  Since then the growth of knowledge regarding this disease has been
almost exponential.

The identification and cloning of the PKD1 gene in 1995, followed by the
discovery of its protein product, polycystin 1, and the sequencing of polycystin
2 in 1996, have led to further significant progress in studying this disease. 
The latter success can be attributed largely to the development of a PKD mouse
model, which has allowed the study of the disease, especially in identifying the
gene for the recessive form, ARPKD.  Numerous mouse cystic kidney mutations have
been described and further exploitation of these mutants and their genetic
modifiers should continue to provide powerful resources to study genes and
genetic interactions involved in PKD.

B.  Research Goals and Scope

Although most recently the major focus of research on PKD has been to identify
the genetic factors that cause the development of cysts and the progression of
cyst-related changes within the kidney, the emphases of this initiative are more
extensive.  Therefore the following research goals are provided as potential
areas of investigation that may be considered in developing innovative studies
in an ICPKD.  These are provided as examples and should not be viewed as
restrictive or all inclusive:

o Genetic Mechanisms:

Define primary and secondary mutagenic mechanisms of PKD1 & PKD2;

Localize and clone genes for other forms;

Identify genetic loci or genes that modify the PKD disease process;

Clone the ARPKD gene;

Develop genomic reagents useful to these goals.

o Biology of Polycystin function

Define the structural topography of PKD1-2 proteins and their interacting
partners;

Define cellular and biochemical functions of PKD1-PKD2 and their downstream
mediators;

Identify genes responsible for renal cystic development and the progression of
renal dysfunction in animal models.

o Physiological Studies

Develop physiological measurements in murine models of PKD;

o Pathogenesis and Progression

Define the basis for increased epithelial proliferation;

Define the role of inflammation in disease progression;

Define the role of the renal microvasculature  in disease progression;

Develop novel markers or end points to monitor the progression of renal
dysfunction in PKD;

Develop means to monitor renal dysfunction before the decline in GFR;

Elucidate control of fluid secretion and accumulation in cysts.

o Innovative therapeutic strategies for ameliorating the initiation of cyst
formation and course of progression of renal dysfunction in humans and in animal
models

Explore treatments based on new pathogenic insights;

Explore innovative therapies to ameliorate the course of disease using
pharmacologic and gene therapeutic approaches in animal models;

Explore innovative therapies to ameliorate the course of disease using
pharmacologic therapeutic approaches in patients;

Identify and initiate innovative treatments in specific cohorts of patients with
unusual clinical characteristics (including extra-renal manifestations of
disease) or rates of progression of renal disease.

Description of a Center

An ICPKD must be an identifiable organizational unit within a single university
medical center or within a consortium of cooperating institutions with a
university affiliation.  The overall goal of an ICPKD is to bring together, in
a cooperative, multidisciplinary and integrative manner, basic science and
clinical investigators to enrich the effectiveness of research on PKD.  To
accomplish the overall goal of these Centers, there should be the existence at
the applicant's institution an ongoing program of excellence in biomedical
research related to the study of kidney disease.  However, the research program
need not be exclusively in kidney, and can include elements related to
development, creation of animal models for use in fundamental studies, and the
development of innovative, pioneering human investigation protocols.  It would
be highly desirable that the Principal Investigator, as well as the applicant
institution, has a commitment to the fundamental investigation for treatment and
prevention of kidney diseases.  Close cooperation, communication, and
collaboration among all participating center personnel of many professional
disciplines are characteristics of a successful ICPKD.

Research Projects

The ICPKD grant consists of a cluster of individual, but interrelated, basic
research projects, each with high scientific merit and clear research objectives. 
In the aggregate, the projects should be directed to the development of
fundamental knowledge leading to understanding of the disease processes and the
design of curative or preventive strategies.  Criteria for designating an
investigator as an ICPKD participant should be defined.  Subsets of participants
based on degree of participation or other measures are acceptable.  Each ICPKD
is encouraged to develop guidelines for ICPKD participation by investigators.

Core Facilities

Core facilities in an ICPKD are shared resources that enhance productivity or in
other ways benefit a group of investigators working to accomplish the stated
goals of the ICPKD.  Cores should be designed to furnish a group of investigators
with some technique, service, determination, or instrumentation in a manner that
will enhance the research in progress, consolidate manpower effort, and
contribute to cost-effectiveness by providing a service at lower cost and
possibly higher quality than if each investigator were to attempt the same
activity individually.  Cores may be proposed in relation to any acceptable
research activity of the ICPKD, but usually fall into one of four categories: (l)
provision of a technology that lends itself to automation or preparation in large
batches (e.g., radioimmunoassay and tissue culture); (2) complex instrumentation
(e.g., electron microscopy or mass spectrometry); (3) animal preparation and
care; and (4) technical assistance and training (e.g., molecular biology).

Examples of possible core resources that would be considered within the scope of
this request for applications include the following:

o  Molecular biology core to supply oligonucleotides and provide automated DNA
sequencing capability;

o  Animal models core to develop, breed, and maintain animal models for diseases
of PKD interest, which can be used to improve understanding of the human forms
of the disease;

o  Tissue culture core for the harvest, cultivation, infection and handling of
large numbers of cells;

o  Other cores needed to characterize gene transfer systems.

These cores are not listed in any particular order, nor should they be construed
to represent a comprehensive list of cores that could be fostered under this
program.

The establishment of and continued support for biomedical research cores within
a ICPKD must be justified on the basis of use by Center investigators.  The
minimum requirement is significant usage by two or more principal investigators
each with a Center project.  A director must be named for each core.  The
organization and proposed mode of operation of each core should be described,
with a plan for prioritizing investigator use of the core as well as the criteria
for determining core users or potential users.

Each core must have in place a procedure to evaluate efficiency and to maintain
appropriate quality control. Limited developmental research is an additional
appropriate function of a core facility, so long as the research is related
directly to enhancing the function or utility of the core and is not an
undertaking that should be funded through other mechanisms.  Teaching the
investigators and/or their staff members' new techniques and methodologies is
also an important function of the cores.  The cores are not intended to supplant
investigator capabilities; rather, they are intended to enhance the opportunities
of investigators to learn and become proficient in the technologies available
through the core.

Other types of activities also may be supported by an ICPKD, including optional
pilot and feasibility (P&F) and enrichment programs.

C.  Pilot and Feasibility (P&F) Program

The P&F program may provide modest support for innovative initiatives with the
potential to advance progress in understanding cellular and molecular mechanisms
of PKD.  This program is directed toward both new/young and established
investigators who wish to explore the feasibility of a novel approach to a
problem in this area.  Investigators eligible for P&F funding fall into three
general categories: (1) new investigators without current or past NIH support as
a principal investigator, and whose current or previous support from other
sources have been modest; (2) established investigators with limited previous
work in PKD who wish to apply their expertise to a problem in this area; and (3)
established cellular and molecular genetics investigators who propose testing
innovative ideas that represent a clear departure from their ongoing research
directions.  It is anticipated that the majority of the recipients of P&F funding
will be from the first category.  However, all eligible investigators must be
independent investigators.  Postdoctoral fellows or their equivalent are not
eligible.

Each pilot and feasibility study award is intended to provide a modest amount of
support, not to exceed $50,000 direct costs, for a duration not to exceed two
years, which will allow an investigator the opportunity to develop sufficient
preliminary data to provide the basis for an application for independent research
support.  P&F study support is not intended for large projects by established
investigators, which otherwise would be submitted as separate research grant
applications.  P&F funds also are not intended to support or supplement ongoing
funded research of an investigator.

Each P&F study proposal should state clearly the justification for eligibility
of the investigator under one of the above three criteria.  A proposed P&F study
should present a testable hypothesis and clearly delineate the question being
asked, detail the procedures to be followed, and discuss how the data will be
analyzed.  The P&F studies should be submitted for review generally in the format
of NIH research project applications (R01), but with a 15-page limitation. The
amount requested for individual pilot and feasibility studies in any given year
cannot exceed 20% of the requested direct cost budget.

Initial Review and Management of P&F Program

Within this structure, each applicant institution must also establish a mechanism
to oversee the use of funds for the proposed P&F program.  This mechanism must
include the use of appropriate consultants (described below) for review from the
scientific community external to the ICPKD.  These same consultants may, if
desired, review and assess other activities of the ICPKD and may constitute the
external advisory group to the ICPKD.  The projects selected to receive these
funds will be described by the Director in the annual progress report and will
be given special attention by the NIDDK in its annual evaluation.

D.  Enrichment and Educational Program

The ICPKD grant can budget for and provide limited support for an enrichment
program, whose description and budget may be included within the administrative
core.  It may provide support for visiting scientists, seminars, and research
forums.  Limited travel support is allowable for ICPKD investigators to travel
to present scientific findings, learn new laboratory techniques, develop new
collaborations, or engage in scientific information exchange.  In all cases, the
enrichment program should further the overall aims and objectives of the ICPKD
as well as of the scientific cores.  Travel funds should be included for an
annual meeting of the ICPKD directors.

Center Administration

An ICPKD will involve the interaction of broad and diverse elements within a
single institution, or a consortium of cooperating institutions; thus the lines
of authority and sanction by the appropriate institutional officials must be
specified clearly.  The administration of the ICPKD will include the
responsibility of coordinating the various functions of the Center.

Program Director

Each applicant institution will specify a Center Director to be responsible for
the organization and operation of the ICPKD.  It would be highly desirable that
the Center Director, as well as the applicant institution, has a commitment to
the investigation of molecular and cellular topics relevant to kidney topics. 
The Center Director should be an experienced and respected individual who can
provide scientific and administrative leadership for the total program.  This
individual must be able to coordinate, integrate, and provide guidance in
establishing new programs in polycystic kidney disease research.  An Associate
Center Director should be named who will be involved in the administrative and
scientific efforts of the ICPKD and will serve as acting director in the absence
of the Center Director.

B.  Internal Executive Committee

It is expected that the administrative organization of the Center will include
a supportive structure, such as an internal executive committee to ensure
accomplishment of (1) Coordinating and integrating the ICPKD components and
activities; (2) Review the use of funds for pilot and feasibility studies; (3)
Provide advice to the Director about the productivity and effectiveness of the
activities of the ICPKD; and (4) Interact with the NIDDK and other appropriate
individuals or groups including the scientific and lay communities, in order to
help develop relevant goals.

The final administrative structure of the ICPKD will, for the most part, be left
to the discretion of the applicant institution (subject to review by the NIDDK). 
The NIDDK's experience has demonstrated that the effective development of an
ICPKD program requires close interaction among the Center Director, the
collaborating investigators, appropriate institutional administrative personnel,
the staff of the awarding agency, and other members of the institution in which
the ICPKD is located.  Therefore, each ICPKD applicant should establish an
administrative structure that will permit the development of such interaction. 
It is desirable for the Center administration to include an administrative
assistant.

C. External Advisory Committee

The formation of an external advisory group to the ICPKD is encouraged.  This
group, comprised of 3-5 members, may advise the Center Director in the areas of
budget, policy, collaborations, or other areas and may provide a scientific
review group for the P&F program.

While facilities (space, equipment, library, etc.) must be described in each
element in the application, a more general description of the overall facilities
and a statement regarding institutional commitment to the ICPKD also should be
included in the description of the administrative organization.

SPECIAL REQUIREMENTS

Successful applicants, during the second year of the award and each year
thereafter, may be expected to attend a yearly meeting of Renal Centers Directors
convened by the NIDDK.  Funds for this activity may be requested in the budget
proposed for the respective center.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-105.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

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

LETTER OF INTENT

Prospective applicants are asked to submit, by March 12, 1999, a letter of intent
that includes a descriptive
title of the proposed research, the name, address, and telephone number of the
principal Investigator, the identities of other key personnel and 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 that it contains 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:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS.37F, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application. Failure to use this
label could result in delayed processing of the application such that it may not
reach the review committee in time for review.  In addition, the RFA title and
number must be typed on line 2 of the face page of the application form and the
YES box must be marked.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be sent
to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS.37F, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after that date, it will be
returned to the applicant without review.  Similarly, supplemental documents
containing significant revision or additions will not be accepted after that
date, unless the Scientific Review Administrator notifies applicants.

The Center for Scientific Review (CSR) 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 CSR
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.

Applicants are encouraged to contact the NIDDK staff as early as possible. 
Consultation between NIDDK staff and potential applicants prior to submission of
the formal application is important.  However, applicants should not construe
advice given by the NIDDK staff as assurance of a favorable review.  The NIDDK
staff will not evaluate or discuss the merit of the scientific aspects of the
application.

Application Content and Format

The instructions provided below modify and expand appropriate sections of Form
PHS 398 to make it applicable for a Center request. These instructions are meant
to be used with the PHS 398 instructions.  It is important to follow the PHS 398
instructions closely.  The "Illustrations" referred to below are suggestions for
representing the information required in a format that has been proven useful in
the submission and review of NIDDK program project applications.  They can be
obtained from the program official listed under INQUIRIES.

Face Page, Page 1: Type "Interdisciplinary Centers for Polycystic Kidney Disease
Research DK 99-012" on line 2.  Complete all items on the face page as directed. 
Items 4 and 5 must have current approval dates.

Description and Key Personnel. Page 2: List key professional personnel and
describe the proposed research program, indicating the major thrust of the
component projects.  Do not exceed the space allowed.

Table of Contents. Page 3 (Illustration 1): Identify each project, each core
unit, the pilot and feasibility program (optional), the budget for each project,
each core unit and the pilot and feasibility program, and supply the page number
for each.  Identify each project by title and assign each project a number that
reflects the order of presentation.  Assign each core a title and a letter
designation.  Use space under section 3 to list each project and core, their page
numbers, and the individual project/core principal investigator.  Number the
following pages sequentially starting with the composite budget.  List any
appendix materials to accompany the application.

Composite Budget: Center applications cannot request more than $750,000 annual
total costs.  A series of composite budgets are to be prepared:

1)  A first-year budget for the Center using the page of Form PHS 398 entitled
"Detailed Budget for First 12-Month Budget Period" (*Illustration 2).

2)  The "Budget for Entire Proposed Project Period" using the appropriate budget
page of Form PHS 398.  The first year of support will reflect the category totals
from "Illustration 2" budget.  Omit budget justifications on this page, but
include them with the individual project budgets.

3)  A breakdown of the composite budget for each requested year as indicated in
*Illustration 3.

4)  Detailed budgets for each category for the first year only.  In the
"Personnel" category, list all professional and non-professional participants in
the program, including those for whom no salary is requested, according to the
format in Illustration 4.  Similarly, present the detailed information for the
remaining categories as specified in the instruction sheets for Form PHS 398.

5)  The P&F program (optional) budget should be included within the
Administrative Core.  There should be a single budget for the P&F program as a
whole rather than individual budgets for each P&F project.  This total P&F
program budget may not exceed 20% of the total direct costs annually.

Biographical Sketch: Updated biographical sketches are required for all
professional personnel.  These should be prepared in accordance with the
directions for Form PHS 398, arranged in alphabetical order, and placed in the
application following the budget section.

Current Sources of Support: Provide a detailed list of the sources of awarded and
pending research support including fellowships and contracts for all
participating investigators.  All funding, including Federal, private, and
institutional, must be identified.  Follow the instructions of Form PHS 398,
which require that each item provides: (a) the source of support, identifying
number and title; (b) percentage of appointment on the project; (c) dates of
entire project period; (d) annual direct costs; (e) a brief description of the
Project; (f) whether the item overlaps, duplicates, or is being replaced or
supplemented by the present application; delineate and justify the nature and
extent of any scientific and/or budgetary overlaps or boundaries; and (g) any
modifications that will be made should the present application be funded. In
addition, summarize these data as shown in Illustration 6 of the appendix.

Overall Research Plan: Using continuation pages, substitute the following for the
Research Plan instructions of Form PHS 398:

1) Program Introduction and Statement of Objectives:

Describe the rationale for the proposed research program.  Explain the strategy
for achieving the objective of the overall program, how each project and core
unit relate to the strategy, and how the projects and cores relate to one
another.

It is important to document prior collaborative arrangements between
investigators in the group, to emphasize the events that have led to the current
application, to predict the anticipated unique advantages that would be gained
by the research within the proposed Center, to describe how the projects are
mutually reinforcing, and to explain how the projects collectively would achieve
the stated objective of the proposed research.

2) Institutional Environment and Resources:

Briefly describe the features of the institutional environment that are or would
be relevant to the effective implementation of the proposed program.  As
appropriate, describe available resources, such as clinical and laboratory
facilities, participating and affiliated units, patient populations, geographic
distribution of space and personnel, and consultative resources.

Organizational and Administration Structure of the Center: Describe in detail,
and by diagram if appropriate, the chain of responsibility for decision-making
and administration.  Describe to whom the principal investigator/program director
reports and the administrative structure as it relates to the individual
project/core principal investigators.

If advisory groups are included, indicate where in the chain of responsibility
they fit and describe the specific functions of these consultants in the overall
program.

3) Specific Managerial Responsibilities:

Indicate who would be responsible for assisting the principal
investigator/program director with the day-to-day administrative details, program
coordination, and planning and evaluation of the program, and who would be in
charge in the absence of the director.

4) Designation of Replacement for Principal Investigator:

Describe procedures for appointing a replacement for the principal investigator
if the need should arise.

5) Relation of the Center Organization and Administration to the Applicant
Institution:

Describe the relationships among the proposed Center and other existing research,
academic, and administrative units of the applicant institution, such as centers,
institutes, departments, and central administration. Indicate if any of the
proposed cores will utilize or expand cores already existing at the institution,
and the benefits that will derive from such an expansion.

Research Projects:

Use a separate Form PHS 398 for each project, and title and number each project
sequentially so that it can be readily distinguished from other projects in the
program.  Each research project should be identified clearly by the same title
as that provided in the Table of Contents.  However, do not submit additional
application face pages.

Each project should begin with abstract and budget pages, which should be
followed by information requested in Sections A through I of the instructions for
Form PHS 398.  Describe each in the same detail and format as required for a
regular research grant application so that the scientific merit can be judged on
the basis of the written application.  For each project, adhere to the
restrictions on number of pages and type size indicated in the instructions for
Form PHS 398.  The total number of pages for Sections A-D must not exceed 25
pages.  Applications exceeding this page limitation will be returned to the
applicant.  As described under "Review Criteria," priority scores will be
assigned to each individual research project as well as to the Center as a whole. 
Thus, the description of each project should be explicit enough to enable experts
in related areas to understand the main thrust of each project without resorting
to appendix materials to provide detailed procedures or critical data.

The budget for each research project should adhere to the instructions from Form
PHS 398.  A detailed budget is required for the first year; budget estimates are
required for all subsequent years of support.  Explicit and detailed budget
justifications must be included for all years. For example, all personnel
positions, regardless of whether dollars are requested, must be clearly
justified.  All listed individuals must have a specified time commitment.

Core Units:

Use a separate Form PHS 398, and name and assign a letter designation to each
unit. Provide a detailed budget for each core in the same way as for each
project.  Describe the core unit and the various services it would provide, as
well as the personnel, facilities, management, and any special arrangements such
as cooperation with other established cores. The core description should include
a clear delineation of procedures, techniques, and quality control, and how core
usage would be prioritized. If applicable, describe in detail statistical
analyses and data management.

Within each core, indicate which core services each project would utilize. In
addition, prepare a table that indicates the research projects each core unit
would serve and the proportion of the cost of the core unit associated with each
research project (see Illustration 5 of the appendix).

Pilot and Feasibility Program (optional):

This program provides modest research support for a limited time (one to two
years) to enable eligible investigators to explore the feasibility of a concept
related to the mission of the Center and generate sufficient data to pursue it
through other funding mechanisms.  As described above, the P&F studies are
intended to:  (1) provide initial support for new investigators; (2) allow
exploration of new leads or new directions for established investigators in
kidney disease; and (3) stimulate investigators from other areas to lend their
expertise to research in PKD.  It is expected that the majority of the
investigators will fall into the first category.  All eligible investigators,
however, must have faculty appointments and be independent investigators. 
Postdoctoral fellows or their equivalent are not eligible.  Each P&F study
proposal should state clearly the justification for eligibility of the
investigator under one of the above three criteria.

A proposed P&F study should present a testable hypothesis and clearly delineate
the question being asked, detail the procedures to be followed, and discuss how
the data will be analyzed.  It must be on a topic related to the objectives of
the Center.  It should be submitted generally using the NIH research project
application (R01) format, but the description of the proposed research should be
limited to five pages.  Projects should be focused, since funding for these
studies is modest and is limited to two years or less.  Any one investigator is
eligible only once for this support, unless the additional proposed pilot and
feasibility study constitutes a real departure from his/her ongoing research.

The application should clearly describe and justify the pool from which potential
pilot and feasibility applications will be selected.  This can be limited to
investigators at the parent institution or expanded to include investigators at
institutions with a well-defined affiliation with the Center.  Such an
affiliation can occur either through a sub-contractual relationship for support
of core resources or projects at a collaborating institution or through another
mechanism supporting established collaboration between investigators of the
Center with investigators at another institution.  The mechanisms by which
information on the availability of P&F awards will be disseminated and by which
applicants will apply and be selected for these awards must be described and will
be an important element in the review of the pilot and feasibility component of
the Center.

A P&F study award is intended to provide modest support which will allow an
investigator the opportunity to develop sufficient preliminary data to provide
the basis for an application for independent research support.  P&F study support
is not intended for large projects by established investigators which would
otherwise be submitted as separate research grant applications.  P&F funds are
also not intended to support or supplement ongoing funded research of an
investigator.

Initial Review and Management of P&F Program

By the very nature of this program, a significant responsibility for its
management will be left to the Center administration during the project periods. 
During the review of the Center grant application, the P&F proposals are reviewed
by the initial review group.  These initial P&F studies must have been reviewed
by the proposed Center management in the manner proposed for review of future
studies, so that only those considered to be the highest quality are included in
the grant application.  The amount of P&F funds provided for the initial year
will be based on the review of the approved studies.  The budget for future years
is recommended by the initial review group based on the quality of the P&F
studies proposed, and the proposed method for management and review (as evidenced
by this set of projects).  Also considered will be the review group's evaluation
of the future justification for continued P&F support.

Since P&F studies can be awarded for any period of time up to two years, studies
end at various times.  In addition, the studies may also be terminated by the
Center administration before their approved time limit for various reasons: for
example, (1) the investigator may receive outside funding for the project; (2)
the project was found not to be feasible; (3) the investigator may leave the
Center institution; etc.  When this occurs, the Center may make new awards for
P&F studies with the remaining funds.

While a Center's administrative framework for management of the P&F program is
left up to each Center (subject to NIH peer review), certain minimal requirements
must be met.  The P&F program must have a director who is an established
investigator in polycystic kidney disease.  There must be a committee
representing all the aspects of the Center, to assist the director in the
management of the P&F program.  Responsibilities of the director and the
committee are to:

(1) Maintain oversight and review of ongoing P&F studies;

(2) Make recommendations regarding termination or other actions to the Center
Executive Committee (or equivalent);

(3) Prepare and ensure appropriate distribution of announcements of the
availability of P&F funding;

(4) Arrange and preside over the scientific merit review of proposals.  At least
one reviewer from outside the parent institution must be used for each proposal. 
All reviewers should assign priority scores in accordance with the NIH system. 
Copies of all of the proposals with written documentation of their reviews,
priority scores, and final action must be retained by the Center.  These records
must be made available to reviewers if requested;

(5) Maintain, insofar as is possible, a record of subsequent career events of
each P&F study recipient;

(6) Make recommendations to the Center Executive Committee (or equivalent) for
final decisions.  A record of actions by this committee must be documented and
be made available if requested by the initial review group.

The Center application should describe how these requirements would be met. 
There also should be an assessment of the relevance of proposed individual P&F
studies and of the program as a whole, to research on PKD and to the specific
goals and objectives of the individual Center and of the NIDDK Center program
generally.

Research Training

Training postdoctoral fellows to conduct research in PKD is an associated
activity of a Center.  While stipends for fellows cannot be provided from Center
grant funds, the establishment of a Center will invariably provide an enhanced
environment for research training.  Just as in the case of funding for individual
research projects, funding for fellowships should be sought from NIH NRSA
institutional training grants (T32, T35) and individual fellowships (F32, F33),
and other sources such as private foundations, and commercial companies.

Although no budgetary items can be included for research training, a section may
be included in Center applications, which documents the potential for research
training program in PKD, its relationship to the Center, and how the presence of
the Center may enhance the program.

Reporting Requirements and Annual Evaluation

Annual progress reports, submitted as part of the annual non-competing
continuation application, are used by the NIDDK and advisory committees to review
the Center and its progress.  These reports serve to verify in detail the
achievement of the objectives outlined in the initial application and award. The
NIDDK staff may, as necessary, assemble consultants to review the progress of the
Center or to discuss major changes in the program that may require budget
adjustments and/or review by the National Advisory Council.

The progress report should describe the progress during the past budget year. 
This expanded progress report does not replace other management reports required
by PHS policy.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIDDK.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  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
accordance with the review criteria stated below.  As part of the initial merit
review, a process will be used by the initial review group in which applications
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 the
applications under review, will be discussed, assigned a priority score, and
receive a second level review by the National Diabetes and Digestive and Kidney
Diseases Advisory Council.

Applications will not be reviewed by a site visit team, and therefore, the
written application should be complete so as to facilitate review without a site
visit.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

Individual Projects

1) 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?

2) 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?

3) 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 technologies?

4) 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)?

5) 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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

O  Appropriateness of the proposed budget and duration in relation to the
proposed research

O  Adequacy of plans to include both genders, minorities and their subgroups, and
children 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 subjects and the safety of the research environment.

Cores

The review criteria for scientific cores include:

The appropriateness and utility of the core to the proposed center; each core
unit must provide facilities or services to at least two research projects
recommended for approval;

The quality of the proposed facilities or services including administrative
arrangements for utilizing the core;

The qualifications, experience, and commitment of the personnel involved in the
core;

The appropriateness of the budget.

Review and Management of the P&F Program

During the review of an ICPKD grant application, the P&F proposals are reviewed
by the initial review group in a manner similar to a study section review. 
Because P&F studies may be awarded for a time period of up to 2 years, studies
may end at various times. In addition, the studies also may be terminated by the
ICPKD Director before their approved time limit for various reasons.  When such
situations result in the termination of the study, the ICPKD may make new awards
for P&F studies with the remaining funds.  The administrative framework for
management of the ICPKD's P&F program is left to the ICPKD's discretion, so long
as certain minimal requirements are met.  Each ICPKD Director is encouraged
strongly to involve the external advisory group in the management of the program. 
The management of the program must include provision for  (1) oversight and
review of ongoing P&F studies; (2) termination of projects or other appropriate
actions; (3) preparation and appropriate distribution of announcements of the
availability of P&F funding; (4) scientific merit review of P&F proposals; (5)
maintenance of a record of subsequent results (abstracts, publications, R01
submissions, etc.) of each P&F study recipient; and (6) a mechanism for making
recommendations to the ICPKD Director for funding decisions. A record of actions
must be documented and must be made available to the reviewers if requested.

Overall Center Program

The review criteria for the overall Center program include:

The scientific merit of the program as a whole;

The significance of the overall goals of the Center;

The cohesiveness and multi-disciplinary scope of the Center and the coordination
and interrelationship of the projects and cores to the common theme of the
Center;

The leadership, scientific expertise, and commitment of the proposed Center
Director.

Center Administrative Considerations

For all Center applications, the review will assess:

The institutional environment for and resources available to Center
investigators;

The institutional commitment to the proposed Center;

The administrative leadership necessary to provide for the quality control of
supported projects in the Center, the allocation of funds and the ability to
foster communication and cooperation among Center investigators.

Schedule

Letter of Intent Receipt Date: March 12, 1999
Application Receipt Date: April 13, 1999
Peer Review Date: June - August, 1999
Council Review: September 8-9, 1999
Earliest Anticipated Start Date: September 30, 1999

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o scientific merit (as determined by peer review)

o availability of funds

o programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions is welcomed.

Inquires regarding programmatic issues may be directed to:

M. James Scherbenske, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS.19E, MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-7719
FAX:  (301) 480-3510
Email:  scherbensk@extra.niddk.nih.gov

Inquiries regarding fiscal matters may be directed to:

Mrs. Helen Y.S. Ling
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN.44F, MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8857

AUTHORITY AND REGULATIONS

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 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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.