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DIABETIC NEPHROPATHY: MECHANISMS, GENETIC DETERMINANTS, INTERVENTIONS

NIH GUIDE, Volume 26, Number 32, September 26, 1997

RFA:  DK-98-001

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  December 9, 1997
Application Receipt Date:  January 9, 1998

PURPOSE

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 pathophysiology of
diabetic nephropathy, the genetic determinants of susceptibility, and
cellular and molecular factors; mechanisms of glomerulosclerosis,
interstitial fibrosis and renal scarring; development of experimental
model systems that mimic human disease to better the understanding of
the pathogenetic mechanisms and to test agents to prevent, stabilize
or reverse complications; identification of sensitive and relevant
markers of disease initiation and progression; identification of
innovative therapeutic interventions and gene targeted strategies to
prevent, limit, or reverse renal lesions due to this disorder. The
intent of the Request for Applications (RFA) is to intensify
investigator-initiated research, to attract new investigators to the
field, and to increase interdisciplinary research to enhance the
scope and effectiveness of research in this area.  The ultimate aim
is to encourage and facilitate diabetes nephropathy-related studies
utilizing new tools and taking advantage of opportunities in other
fields to increase the pace with which knowledge is accrued.

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,
"Kidney Disease of Diabetes: Mechanisms, Genetics, 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).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic and foreign
for-profit and non-profit organizations, public and private, such as
universities, colleges, 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.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) Research Project Grants (R01), Interactive Research
Project Grants (IRPG), FIRST Award (R29), and Exploratory Research
Grants (R21) award mechanisms.  FIRST Award applications must adhere
to the R29 administrative guidelines (rev. June 1995) for
eligibility, budget, and period of award.

Applications from Institutions with 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.

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  Awards will
be administered under Public Health Service (PHS) grants policy as
stated in the PHS Grants Policy Statement.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures. Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  For R01s, the total requested project period for
applications submitted in response to this RFA may not exceed 5
years.  A maximum of three-years can be requested for foreign awards.
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.  Applicants
anticipating submitting Interactive Research Program Grant (IRPG)
Applications should consult with the Program Official listed under
"INQUIRIES" at an early opportunity. Applications for Exploratory
Research Project Grant Applications (R21) awards may apply for no
more than $50,000 direct costs per year, for a maximum of two years.
The anticipated award date is July 1, 1998.

FUNDS AVAILABLE

A total of $ 2.5 million in total cost will be committed by the NIDDK
to fund applications of high scientific merit submitted in response
to this RFA.  It is anticipated that 10-12 awards will be made.
Although this program is provided for in the financial plans of the
NIDDK, the award of grants pursuant to this RFA is also contingent
upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background:

Diabetic nephropathy has emerged as the largest single cause of end
stage renal failure in the United States. It accounts for nearly 40%
of the 60,000 to 70,000 new patients who need dialysis each year.
Diabetic patients do poorly on dialysis, with high rates of
infection, access failure, and cardiovascular complications.  Of all
long-term complications of diabetes, nephropathy imposes the highest
costs, both in dollars and in terms of human suffering.

Concerning the genetic implications, diabetic nephropathy does not
necessarily develop in all diabetic patients, the incidence of end
stage renal failure being about 30% in patients with
insulin-dependent diabetes mellitus (IDDM) and approximately 4-20% in
patients with non-insulin-dependent diabetes mellitus (NIDDM). There
is now strong evidence that genetic factors influence susceptibility
to this condition.  A variety of new strategies are available to
characterize the genetic determinants for the development and
progression of diabetic nephropathy.  Included are the identification
of new candidate susceptibility genes using methods of molecular
genetics such as differential display or others; examination of the
role of putative candidate genes in the onset and progression of
diabetic nephropathy using family studies and transmission
disequilibrium testing (TDT); identification of chromosomal regions
containing genes responsible for susceptibility through family
(linkage) studies and, potentially, once such regions are identified,
positional cloning of the putative genes, etc.

Concerning the pathophysiology of the disease, new insights also
suggest new productive avenues for research.  In virtually all
patients, diabetes mellitus initially leads to diffuse renal
hypertrophy and basement membrane thickening.  Much early
investigation focused on the pathogenesis of these lesions.
Progression of these early markers is highly variable, however.  In
many patients, the early lesions are not followed by the development
of glomerular scarring.  Much of the available evidence suggests that
scarring of the glomerulus arises from interactions between the
microvasculature and the surrounding cell types. Specific topics
needing further study include the mechanism by which hemodynamic
factors potentiate injury, the role of cytokines and growth factors
in regulation of scarring, particular stress responses, role of the
renin-angiotensin system and aldosterone, the role of epithelial
cells in the genesis of glomerular injury, the elucidation and
characterization of the biochemical composition of the expanded
matrix in diabetic nephropathy, the role of the polyol pathway
activity, non-enzymatic glycation, advanced glycosylation
end-products (AGES), redox changes, formation of reactive oxygen
species, and the possible interrelationship of the mechanisms listed
above in different cell types and tissues and in the different stages
of the natural history and progression of diabetic nephropathy.

Further work is needed in the development of animal models which
mimic human disease, as well as models using genetically modified
mice in which the effect of over- or underexpression of candidate
susceptibility genes is examined. This may permit direct examination
of genetic factors which determine the development and progression of
the renal injury.

Concerning the need to identify markers which will permit early
identification of patients at risk of developing renal disease, the
best currently available clinical tool for early identification of
diabetic nephropathy remains the quantitative assessment of urinary
albumin excretion. Prospective epidemiological information is needed
to assess the predictive value of this measure, together with other
clinical parameters in various population groups.

Scientific Objectives:

(1) To identify genes whose altered function predispose to diabetic
nephropathy and to understand the mechanisms by which these genetic
alterations enhance susceptibility.

(2) To understand the underlying mechanisms leading to progressive
renal scarring in diabetic nephropathy.

(3) To identify markers which will permit early identification of
patients at increased risk for diabetic nephropathy.

Research Scope:

It is the intent of this solicitation to invite applications from
investigators with diverse scientific interests, who wish to apply
their expertise to basic and applied research to enhance the
understanding of the pathophysiology and pathogenesis of diabetic
nephropathy; the genetic determinants and genetic factors influencing
susceptibility, and cellular and molecular mechanisms and interplay
that lead to the development of glomerulosclerosis and
tubulointerstitial fibrosis and scarring; the development of
experimental model systems in which the expression of susceptibility
genes is examined; the identification of markers to ascertain when
the process starts and when disease progresses; the identification of
therapeutic opportunities and potentially gene targeted strategies to
prevent or control scarring and progressive renal insufficiency in
diabetic nephropathy.

Examples which 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. Pathogenetic Mechanisms

o  Role, mechanisms of action and interplay of growth factors and
other cytokines in regulating glomerular and interstitial sclerosis
and scarring; studies addressing molecular elements of relevant
signaling pathways.

o  Definition of the sequence of events in the pathophysiology of
diabetic nephropathy, at the molecular and cellular levels and
characterization of the molecular elements of relevance in signaling
pathways.

o  Pathobiology of glomerular epithelial cells as well as role of
glomerular endothelial cells, in-vivo, as players in the injury
process.

o  Interaction between the microvasculature and the surrounding cell
types in glomerulosclerosis, tubulo-interstitial fibrosis and
scarring, in diabetic nephropathy.

o  Effect of insulin therapy and counter regulatory hormones on
glomerular and interstitial sclerosis and extracellular matrix
synthesis, composition, and response.

o  Interrelationship of biochemical mechanisms leading to matrix
expansion and the development of scarring in diabetic nephropathy,
including, but not limited to the polyol pathway activity, advanced
glycosylation end-products (AGES), redox changes and formation of
reactive oxygen species in different cell types and tissues in the
different stages of diabetic nephropathy.

o  Role of hemodynamic and vasoactive factors, renin-angiotensin
system, aldosterone and inhibitors, with an effect either over
vascular tone or as trophic factors affecting mRNA expression for
extracellular matrix components and vascular smooth muscle
proliferation.

o  Identification and characterization of susceptibility factors for
renal sclerosis and of putative risk factors for the onset of
microalbuminuria and progression of diabetic nephropathy.

2. Genetic Considerations

o  Identification and characterization of genetic determinants for
the development and progression of human diabetic nephropathy.

o  Identification of new candidate susceptibility genes using methods
of molecular genetics such as differential display or others.

o  Role of putative candidate genes in the onset and progression of
diabetic nephropathy using family studies and transmission
disequilibrium testing.

o  Identification of chromosomal regions containing genes responsible
for susceptibility through family (linkage) studies and potentially,
once such regions are identified, positional cloning of the putative
genes, etc.

3. Therapeutic Strategies

o  Identification of early quantitative markers of disease and
sensitive markers of progression, and identification of adequate
outcome measures to judge the effect of clinical interventions in
early stages of the disease.

o  Identification of novel interventions and new targets for
prevention and treatment of renal fibrosis in diabetic nephropathy.
Mesangial deposition seems to be reversible and glycosylated proteins
remain biodegradable, offering hopes for future therapy.

o  Gene therapy and sequence-specific methods for modifying gene
expression in the kidney; development of techniques suitable for
modifying expression of gene products that accelerate progression of
diabetic nephropathy.

o  Trial of agents that prevent, stabilize or reverse complications
in animal models of diabetic nephropathy.

4. Markers

o  Identification of markers for early recognition of diabetic renal
disease in patients at increased risk  for diabetic nephropathy.

o  Identification of sensitive and specific surrogate end-points for
the development of diabetic nephropathy, other than GFR and albumin
excretion which, are either non-specific or not sensitive enough.

o  Formulation of prospective epidemiologic strategies to assess the
predictive value of quantitative markers, together with other
relevant clinical parameters in various  population groups.

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 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 20, 1994 (FR 59 14508-14513) and reprinted
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.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 9, 1997, 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. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and 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.

Applicants for FIRST (R29) awards must submit at least three letters
of reference, with the application.  FIRST (R29) award applications
received without the three reference letters will be returned to the
applicant.

The RFA label available in the PHS 398 (rev. 5/95) 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, plus three signed photocopies, in one package to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At 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 January 9, 1998.  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 previously reviewed, but such applications must include
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Applications will be reviewed for completeness by DRG and
responsiveness by the NIDDK.  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 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 will be discussed, assigned a priority
score, and receive a second level review by the National Diabetes and
Digestive and Kidney Diseases Advisory Council.

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 review, comments on the following aspects of
the application will be made 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 the assignment of the overall score.

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
technologies?

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.

For applications awarded to foreign institutions:

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.

AWARD CRITERIA

Applications recommended for funding will considered on the basis of
the following:

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

INQUIRIES

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 and Digestive and Kidney Diseases
45 Center Drive, Room 6AS13 - 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
Building 45 Room 6AN-38
45 CENTER DR MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8862
FAX: (301) 480-3504

SCHEDULE

Application receipt dates, initial review, and award cycles will be:

Letter of Intent Receipt Date:  December 9, 1997
Application Receipt Date:       January 9, 1998
Initial Review Date:            March-April 1998
Advisory Council Review:        May 1998
Anticipated Date of Award:      July 1, 1998

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 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.