DIABETIC NEPHROPATHY: MECHANISMS, GENETIC DETERMINANTS,
INTERVENTIONS 

NIH GUIDE, Volume 26, Number 32, September 26, 1997 (see NOT-DK-05-001)

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.


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