Full Text HL-95-004

THE ETIOLOGY OF EXCESS CARDIOVASCULAR DISEASE IN DIABETES MELLITUS

NIH GUIDE, Volume 23, Number 35, October 7, 1994

RFA:  HL-95-004

P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Diabetes 
  Etiology 
  Pathogenesis 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 6, 1995
Application Receipt Date:  April 11, 1995

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) and the Juvenile
Diabetes Foundation International (JDFI), invite applications for
program project grants for research on the etiology of cardiovascular
diseases (CVD) associated with diabetes mellitus.  This initiative will
support investigators with outstanding programs of basic and human
subjects research on one or more diabetes associated cardiovascular
complications.  In addition, these programs, with the encouragement of
the NHLBI, will participate in a coordinated effort to evaluate the
metabolic and environmental factors responsible for the pathogenesis of
CVD in existing, defined population groups.

A program project grant is for the support of a broadly-based
multidisciplinary or multifaceted research program that has a specific
major objective or central theme.  Each program project application and
award in response to this solicitation must have both basic research
and human subjects components.

Applications should be submitted to and will be reviewed by the
National Institutes of Health (NIH) according to the usual NIH peer
review procedures.  Applications judged meritorious will be jointly
funded by NHLBI and JDFI.  To have an application reviewed and
considered for funding by the JDFI, applicants must authorize the NHLBI
in writing to provide a copy of their letter of intent, application,
and NIH prepared summary statement of the initial review to the JDFI.

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, The
Etiology of Excess Cardiovascular Disease in Diabetes Mellitus, is
related to the priority areas of heart disease and stroke, and diabetes
and 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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local government and
eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.  While program project
awards cannot be made to foreign institutions, a subproject of high
scientific merit may be eligible for support.

Exclusions

This RFA is intended to support program project grants that have both
a basic research and human population component.  Therefore,
applications that include only basic or only clinical research will not
be responsive to this announcement.  This solicitation is intended to
redress the inadequate information on the etiology of excess
cardiovascular disease in patients with diabetes mellitus and
applications that do not focus on this aspect of diabetes and
cardiovascular disease will not be considered.  Large population
studies or large clinical trials will be considered unresponsive to
this RFA.  Program Project awards are not made to foreign institutions.
Under exceptional circumstances, a foreign component critical to a
project may be included as a part of that application.

MECHANISM OF SUPPORT

It is the intention of NHLBI and JDFI to stimulate collaboration among
investigators with different but complimentary areas of expertise.
This research will be supported by the NIH program project research
grant mechanism (P01).  Responsibility for planning the proposed
project will be solely that of the applicant.  The total project period
for applications submitted in response to the present RFA may not
exceed 58 months.

A program project grant is for the support of a broadly-based
multidisciplinary or multifaceted research program that has a specific
major objective or central theme.  The award may support research
components and core functions.  Collectively, these components should
demonstrate essential elements of unity and interdependence and result
in a greater contribution to program goals than if each activity were
pursued individually.  Each applicant will be expected to propose
studies containing both basic and human subjects based research
components with concentration on one or more major risk factors as they
relate to the increased risk of CVD in diabetic patients.  Efforts will
be made by the NHLBI to facilitate collaboration both during
development of applications and after the program is established.

The principal investigator should be an established research scientist
with the expertise and experience to provide scientific leadership,
ensure quality control, and effectively administer and integrate all
components of the program.  A minimum time commitment of 25 percent is
expected for this individual.  The principal investigator must also be
the project leader of one of the component research projects.  If,
through peer review, this project is not recommended for further
consideration, the overall Program Project application will not be
considered further.  If this project is judged by peer review to be of
low scientific merit, it will markedly reduce the overall scientific
merit ranking assigned to the entire application by the review
committee.  Project leaders must agree to commit at least 20 percent
effort to each project for which they are responsible.

Applications must be prepared and awards will be made according to
NHLBI Program Project policies.  NHLBI Guidelines for the preparation
of Program Project Grant applications may be obtained from Dr. C.James
Scheirer at the address listed under LETTER OF INTENT.  Approximately
50 percent of the total costs of each grant will be funded by the NHLBI
and the same amount by the JDFI.  Funding rules, including the
determination of allowable indirect costs, will take into consideration
those of each sponsor.  Post award administration will be according to
current policies and requirements that govern the research grant
programs of the NIH and the JDFI as appropriate.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
program project grant application, but it is imperative that a
consortium application be prepared so that the programmatic, fiscal,
and administrative considerations are explained fully.  The published
policy governing consortia is available in the office of sponsored
research of institutions that are eligible to receive Federal
grants-in-aid.  Consult the latest published policy governing consortia
before developing the application.  If clarification of the policy is
needed, contact William Darby, (301) 594-7458.  Applicants for program
project grants should clearly describe the interactions of the
participants and the integration of the consortium project(s) with
those of the parent institution, because synergism and cohesiveness can
be diminished when projects are located outside the group at the parent
institution.  Indirect costs paid as part of a consortium agreement are
excluded from the limit on the amount of direct costs that can be
requested.

In order to more evenly distribute administrative workload and reduce
the number of awards with July 1 or September 30 start dates, the NHLBI
will award ten months of time and money for the first competing budget
period of this project. This action results in a project period of 58
months rather than 60 months.  Investigators should plan their research
projects and budgets within these timeframes.

Although multidisciplinary approaches are required, it is not the
intent of this RFA to solicit applications for large clinical trials or
large epidemiological studies.  In general, funds will not be provided
to purchase and install expensive new equipment.

Support will be provided for up to 58 months.  Continued funding will
be contingent on satisfactory completion of proposed investigations.
In addition to a continuing series of reports on results of individual
investigations, an overall report will be produced at the conclusion of
the program.

FUNDS AVAILABLE

Approximately $1.8 million in total costs will be provided for the
first year of support for the program by NHLBI with an equivalent
amount provided by JDFI.  Applicants may request up to $650,000 direct
costs, not including indirect costs for collaborating institutions, in
the first year with a maximum increase of no more than four percent in
each additional year requested in the application.  Funding rules,
including the determination of allowable indirect costs, will take into
consideration those of each sponsor.  It is anticipated that three to
five grants will be awarded under this program.  Although this program
is provided for in the financial plan of the NHLBI, award of grants
pursuant to this RFA is contingent upon receipt of funds for this
purpose.  Administrative adjustments in project period and/or amount of
support may be required at the time of the award.

Equipment is included in the budget limitation.  However, requests for
special equipment that cause an application to exceed this limit may be
permitted on a case-by-case basis following staff consultation.  Such
equipment requires strong justification.  Final decisions will depend
on the nature of the justification and the availability of funds.

RESEARCH OBJECTIVES

Background

Additional investigations of the etiology of macrovascular
complications of diabetes mellitus are needed.  Such studies should
include populations, clinical research and basic research and involve
experts in both diabetes and cardiovascular diseases.  JDFI has
embarked on a major long term capital fund raising campaign to
establish programs of excellence in diabetes research.

Diabetes mellitus is a complex metabolic disorder that affects not only
glucose metabolism but several other metabolic processes.  Some of
these effects are acute and appear related to concentrations of glucose
and/or insulin.  Other effects develop over many years and are related
to other metabolic derangements of diabetes or are of uncertain
etiology.  Recent advances in understanding the process of
atherogenesis and the pathogenesis of chronic diabetic complications
indicate that diabetes may accelerate atherosclerosis and the
development of clinical cardiovascular disease through several
mechanisms.

The association between overt diabetes mellitus and excess risk of
cardiovascular disease (CVD) has been documented in diabetic
populations throughout the world but the pathogenic mechanisms for the
relationship are only partially understood.  Among diabetic patients,
both the incidence and mortality rates from myocardial infarction are
increased, as are the risks of recurrent infarction, congestive heart
failure, cerebrovascular disease, and peripheral vascular disease.  The
increased risk of CVD associated with diabetes appears to be greater in
women than in men.  In general, about 50 percent of excess heart
disease in diabetics is attributed to associated abnormalities in other
known CVD risk factors but levels of these factors may be in part
determined by the degree of diabetic control.  Milder abnormalities of
glucose tolerance are also associated with an increased risk of
cardiovascular disease, but glucose level in this group generally has
not been an independent CVD risk factor.  In these patients, an
underlying multiple risk factor syndrome may be a major contributor to
accelerated macrovascular disease.

Approximately 12 to 14 million Americans have diabetes and up to an
additional 18 million are estimated to have impaired glucose tolerance,
or glucose levels between diabetes and normoglycemia.  Cardiovascular
disease is the cause of death in 60 to 75 percent of this combined
group.  Insulin dependent diabetes mellitus (IDDM) is a leading cause
of premature cardiovascular disease.  Non-insulin dependent diabetes
(NIDDM) is a significant risk factor for cardiovascular disease in
middle and older ages.  As the U.S. population ages, the importance of
glucose intolerance as a risk factor for CVD will increase since its
prevalence increases markedly with age, reaching over 50 percent in
those above age 65 years.  Moreover, with improved methods of glucose
control, the anticipated decline in chronic microvascular complications
of diabetes may be offset by an increase in the rates of major
cardiovascular complications.

It is not clear whether the pathogenesis of excess CVD is the same in
IDDM and NIDDM.  It is also important to recognize that improved
glucose control in diabetic patients may not by itself be sufficient to
eliminate the excess risk of diabetic cardiovascular complications.
Although recent data from the Diabetes Control and Complication Trial
(DCCT) suggest a reduction in cardiovascular events in the group
achieving near normoglycemia, the numbers of CVD events in this
generally young cohort are small.  Preliminary results from a pilot
study of intensive treatment of hyperglycemia in Type II diabetic
veterans fail to suggest any short term benefit of improved glucose
control, showing fewer cardiovascular events in the conventional than
in the intensive treatment group.  No relative reduction in CVD was
observed in the variable dose insulin treated group of the University
Group Diabetes Program that achieved the best degree of glucose
control.  These observations may be particularly relevant to the Type
II diabetic patient with the multiple cardiovascular risk factor
syndrome (Syndrome X of Reaven) where control of hyperglycemia only
partially ameliorates the other CVD risk factor abnormalities.
Finally, the relative benefits of glucose control and other CVD risk
factor control may vary depending upon the race and gender of the
patient and whether or not atherosclerotic disease is already advanced.
Thus, the treatment most appropriate to prevent long term macrovascular
complications in a young Type I diabetic with labile hyperglycemia may
not be best for an elderly Type II diabetic with mild hyperglycemia.
More information is needed in all of these areas to design better and
more specific treatment and prevention regimens.

Available data on hyperglycemia and insulin levels as risk factors for
CVD have numerous limitations.  Many of the frequently cited studies
are old and utilized techniques of risk factor and disease measurement
that are crude by today's standards.  Until recently, most population
studies of diabetes have included only rudimentary measures of vascular
disease.  Many studies of CVD and associated risk factors measured
diabetes crudely and, in others, particularly several large clinical
trials, diabetics were excluded.  Among several early studies that
indicated a risk for CVD associated with hyperglycemia, it is now
probable that at least part of the risk can be explained by
subsequently identified risk factors that were not measured at the time
of the studies, such as hyperinsulinemia, elevated insulin resistance,
abnormalities in coagulation factors, platelet function, or lipoprotein
particle size or composition.  In fact, two of the frequently cited
studies indicating elevated insulin level is an independent risk factor
for CVD did not measure HDL-cholesterol.  The relative importance of
hyperglycemia, hyperinsulinemia, and elevated insulin resistance as
factors in the excess CVD of diabetes has not been assessed in
prospective studies. Relative to studies on other major CVD risk
factors such as hypertension and hypercholesterolemia, evaluations of
the role of glucose intolerance and its related abnormalities as causes
of CVD have been limited.

The multiple complex metabolic abnormalities associated with diabetes
and their potential interactions with risk factors for atherosclerosis
make collaboration between investigators with differing expertise
essential.  While diabetes increases the risk of CVD in all populations
studied, the observed CVD event rates vary widely, suggesting that
important environmental and probably genetic factors may modify the
adverse effects of hyperglycemia.  Collaboration between experts in
cardiovascular disease and diabetes and among basic researchers,
clinical investigators, and epidemiologists will be essential to
maximize progress in understanding the causes of cardiovascular disease
among diabetic patients and to develop new therapeutic approaches for
preventing this major chronic complication.

Objectives

The primary objective of this initiative is to understand how the
presence of diabetes increases the risk of cardiovascular disease.  To
accelerate this understanding, this initiative will bring together
basic, clinical, and population based investigators to develop a
research program to address this question at the laboratory, clinical,
and population levels.  While the control of hyperglycemia is clearly
associated with a reduction in the development of microvascular
complications of diabetes, its role in the prevention of the
macrovascular complications of diabetes is less certain.  As a
consequence, optimal interventions to prevent these two major
categories of complications may differ.  Proposed studies should focus
on how diabetes increases the risk of macrovascular disease and the
relative importance of hyperglycemia compared to other cardiovascular
disease risk factors associated with glucose intolerance in the
pathogenesis of the macrovascular disease in diabetic patients.

Key questions include:

o  Does hyperglycemia directly cause the macrovascular disease?

o  Does hyperglycemia increase the risk of macrovascular disease
primarily by altering other CVD risk factors?

o  Is the excess risk of CVD in diabetics largely independent of the
level of glucose?

o  Does hyperglycemia have differing importance as a CVD risk factor in
Type I (insulin dependent) compared to Type II (non-insulin dependent)
diabetic patients?

o  Is the observed variation in rates of cardiovascular complications
among diabetic patients in different populations secondary to genetic
and/or environmental factors?

Answers to these questions will be important in formulating
recommendations for therapy of diabetic patients and, potentially, for
the design of a future clinical trial to prevent diabetes associated
CVD.  Investigators selected for participation in this program will be
expected both to direct innovative research at their individual
institutions and to collaborate with other members of the study group
in order to apply this information to human populations.

This initiative will support a broad program to understand the etiology
of the accelerated macrovascular disease found in diabetic patients.
It will not necessarily support investigations in all relevant areas
but attempt to select and to promote collaboration among the most
promising applicant groups.  Applicants will be selected for
participation based upon the overall evaluation of the importance and
innovative aspects of their proposed program and their plans for
evaluating these findings in defined populations.

Specifically, this initiative may support research in several areas,
for example:

o  To evaluate the roles of hyperglycemia, glycosylation of proteins,
and advanced glycosylation end products (AGEs) in the development of
diabetic macrovascular disease.

o  To evaluate the role of hypertension and its interactions with other
risk factors in the development of diabetic macrovascular disease.

o  To evaluate the role of modifications of lipids and lipoproteins
(oxidation and glycosylation) with the development of diabetic
macrovascular disease

o  To evaluate the role of altered coagulation factors, abnormalities
in platelet function, and alterations in blood viscosity in the
development of diabetic macrovascular disease.

o  To evaluate the role of hyperinsulinemia and/or insulin resistance
in the development of diabetic macrovascular disease.

o  To evaluate the role of vascular wall factors in the development of
vascular disease in the presence of hyperglycemia.

o  To evaluate the role of the co-occurrence or "clustering" of CVD
risk factor abnormalities including hypertension, dyslipidemia,
hyperglycemia, and obesity in the development of diabetic macrovascular
disease.

o  To evaluate the role of genetic and environmental factors in the
variation in prevalence of diabetic macrovascular disease among racial
and ethnic groups.

A unique aspect of this initiative is the recognition that much
relevant work on the pathogenesis of atherosclerosis has been conducted
that has not yet been related to the link between diabetes and
atherosclerosis.  A goal of this initiative is to establish
collaborations among groups who have been pursuing separate paths.  For
example, extensive work on lipid oxidation has taken place, the
importance of this process in diabetes has been recognized, but
research to assess its importance in diabetic vascular disease is
limited.  Similarly, extensive work has been done on insulin and
insulin resistance.  The potential importance of these factors in the
multiple CVD risk factor syndrome and in atherosclerosis has been
recognized, but research to assess their atherogenicity in the diabetic
is limited.  Many additional examples were evident in the presentations
at the 1992 Workshop on Diabetes and Mechanisms of Atherogenesis (Getz,
1993).

Advances in basic research during the past decade have greatly improved
understanding of the metabolic abnormalities of diabetes and the
process of atherogenesis.  Further work may lead to unique ways of
preventing or treating the atherosclerosis associated with diabetes.
Because of this, a major portion of this initiative will be devoted to
advancing fundamental knowledge of the atherosclerotic process in
diabetics and to clarifying whether the same processes are responsible
for the excess risk in all diabetic patients.  A key question is
whether the process in diabetic patients is the same or different from
that in nondiabetics.  Multiple research opportunities were identified
in the workshop mentioned above (Getz, 1993).  Many are interrelated.
Several areas appear appropriate for emphasis:

Dyslipidemias and diabetes:  Prevalence rates of cardiovascular disease
are low among diabetic patients in populations with low levels of total
and LDL cholesterol.  Multiple studies have shown alterations in the
levels and composition of lipid particles in diabetic subjects.  In
addition to the long recognized abnormalities such as elevated
triglyceride and lowered HDL-cholesterol levels, numerous other
abnormalities including changes in lipoprotein particle size and
composition, protein glycosylation and oxidation of lipoproteins have
recently been reported.  While the basic lipid changes have been found
in all populations studied, their magnitude varies considerably, both
within groups and within individual diabetic patients, suggesting the
effects of diabetes can be substantially modified by environmental or
underlying genetic factors.  The reasons some individuals and groups
appear to be protected are unknown and represent a promising area for
further investigations.  Lipid metabolism is also an area where
differences occur between Type I and Type II diabetic patients with
more adverse alterations generally found in Type II diabetic patients.

Hypertension and diabetes:  Hypertension is more common in diabetic
patients than in age-matched normoglycemics and its presence increases
the risk of both micro- and macrovascular complications of diabetes.
Many questions need further exploration in this area including the
origins of the excess hypertension.  The relationship of elevated blood
pressure to subclinical renal disease and to the multiple CVD risk
factor syndrome are promising areas for further investigation.  In
addition, recent studies have suggested that the choice of drugs to
treat hypertension may be important in postponing both micro- and
macrovascular complications of diabetes.  The role of renal dysfunction
and the significance of microalbuminuria as a predictor of both micro-
and macrovascular disease needs to be evaluated.

Hemostasis and diabetes:  Multiple abnormalities in the coagulation
system of diabetics have been identified.  Abnormalities include
changes in level and structure of coagulation factors, alterations in
platelet function, and alterations in blood and plasma viscosity.  Many
of the studies are small and the techniques used for measurement were
sometimes controversial.  The associations among coagulation factors
and other recognized CVD risk factors require clarification.  This is
one of the least explored areas of diabetes associated CVD risk but
potentially very important and much work remains to be done.

Hyperglycemia, insulinemia, and insulin sensitivity and diabetes:
These risk factors have generally been the province of diabetologists
studying the development of diabetes but recent reports have suggested
they may be independent cardiovascular disease risk factors.  Critical
questions center around the absolute and relative importance of each of
these factors in the acceleration of atherosclerosis.  If hyperglycemia
is "atherogenic", then improved blood glucose levels should lead to a
decrease in the risk of CVD.  In contrast, if hyperinsulinemia is
"atherogenic," improvement of blood glucose levels by intensive insulin
treatment may reduce the risk of microvascular disease (as demonstrated
in the DCCT) but might increase the risk of macrovascular disease.
Treatment regimens may have different effects in Type I and Type II
diabetic patients.

Vascular biology:  The past decade has produced major advances in our
understanding of atherogenesis at the cellular and molecular level.  It
is now recognized that the vascular endothelium is a complex organ that
senses its environment and responds in numerous ways to injury and to
recognized CVD risk factors.  Independently, major advances have
occurred in understanding how diabetes produces modifications at the
cellular and molecular level.  Much less is known about how these
diabetic modifications may interact with other atherogenic factors in
the local environment of the vessel wall to initiate and propagate
atherosclerotic plaques in diabetic patients.  In fact, it is not known
whether atherosclerosis in diabetics is simply a more rapidly
progressing common atherosclerotic plaque or whether differences exist
in its composition and in the pattern of cellular responses and gene
expression.  An area of particular opportunity is the study of the
regulation of growth factor and cytokine expression by mildly oxidized
low density lipoprotein and advanced glycosylation end products (AGEs).

Genetic and Environmental Factors:  Rates of diabetic macrovascular
complications vary widely in different populations.  For example, some
American Indian tribes, despite extraordinary rates of diabetes, appear
relatively protected against cardiovascular complications.  Some
potential explanations for these differences have been outlined above.
Clarifying the effects of genetic and environmental factors on risk
factor levels (and/or composition) and on the susceptibility of the
vascular wall to atherosclerosis is of critical importance for the
design of future preventive measures.

In addition to improving understanding of the basic processes that lead
to excess macrovascular disease in diabetic patients, a major goal of
this initiative is to apply this information to human studies.  This
initiative will also provide support for limited clinical and
population studies that can either enhance understanding of the
pathophysiology of cardiovascular complications of diabetes or provide
information important for developing new therapeutic interventions.
Because of their cost, support for establishing new epidemiologic
studies of populations or clinical trials to test reduction of disease
risk cannot be provided through this initiative.

The NHLBI has already established several large populations to study
risk factors for cardiovascular disease.  Many of these studies have
collected information on glucose tolerance and historical information
on diagnosis and treatment of diabetes.  They include extensive
characterization of CVD risk factors and assessments of clinical and
subclinical cardiovascular disease, making it possible to describe risk
factor patterns prior to their alteration by drug therapy or clinical
disease.  In addition, these studies include men and women and
representatives of multiple racial and ethnic groups, providing an
opportunity to look at the contrast in risk of cardiovascular
complications among different diabetic groups.  Overall, they represent
a valuable resource for studies of cardiovascular complications in Type
II diabetic patients.  Other important populations have been identified
and characterized with support from other funding sources.  Some
include substantial numbers of Type I diabetic patients.  Investigators
applying for support from this initiative are strongly encouraged to
propose collaborative efforts with existing population studies since
this will be the most efficient way to develop a clinical component.
Investigators are free to propose other clinical components, especially
if they offer unique advantages.  To obtain further information on
NHLBI supported population studies, contact Dr. Peter Savage at the
address listed under INQUIRIES.

It is anticipated that each program project will have several discrete
subprojects conducted by multiple investigators under the overall
direction of the Principal Investigator.  Each application should
include laboratory investigations and also include a clinical and/or
population component.  Studies initiated in one of these components
should lead to application in the others.  For example, lipid
abnormalities described in a population study could be studied further
in the laboratory using cell or animal models then translated into
small clinical trials of drug efficacy.  Other examples could involve
investigations of the effects of hyperinsulinemia or elevated insulin
resistance which include studies of their effect on the isolated
vascular wall lesion, induction of hyperinsulinemia in animal models,
pharmacologic alteration of levels of insulin resistance in small
clinical studies, and assessment of the relative importance of insulin
and insulin resistance on other risk factors in population studies
containing several racial or ethnic groups.  Such examples are not
meant to suggest specific studies but to indicate the spectrum of
research and type of collaboration which this initiative is designed to
support.

In most cases, human subjects will be selected from an existing
population on the basis of previously measured evidence of clinical or
subclinical disease or risk factor profiles.  In many cases such
studies may be conducted on stored samples.  For more complex tests
requiring extensive subject participation or collection of additional
samples, care must be taken to not interfere with the ongoing study.
Existing policies in current multicenter population studies for
approval and reporting of ancillary studies will apply.  NHLBI Project
Scientists will expedite the collaborative aspects of study design and
will facilitate joint research with existing NHLBI funded studies, as
appropriate.

SPECIAL REQUIREMENTS

To facilitate development of applications, NHLBI and JDFI will sponsor
a pre-application information meeting to provide interested
investigators with background information about relevant ongoing
studies using defined human populations and with an opportunity to meet
with individuals involved with this research.  Possibilities for
interdisciplinary efforts will be discussed and individual
investigators will be able to explore ways to apply laboratory findings
to clinical or population samples.  Potential investigators for this
initiative will be encouraged to contact the respective NHLBI Project
Scientist to determine if proposed clinical measurements could be
conducted on a sample from one or more of the existing populations.
Potential applicants are encouraged to attend but no NIH funds will be
provided to attend this meeting.

Upon initiation of this program, the NHLBI and JDFI plan to sponsor a
meeting to encourage the exchange of information among investigators,
to foster collaborative efforts among program grantees, and to identify
resources that would enhance the productivity of several grantees.  In
many cases, combining proposed measures in highly characterized
population subgroups may provide the most information.  Where
appropriate, additional joint protocols will be developed.  After this
planning phase, collaborative investigations will be conducted.
Subsequent meetings will take place approximately yearly.  For this
purpose, requests for travel funds for a two-day meeting (two in year
01 and one per year thereafter) should be included in the budget
section of the application (assume meeting will be held in Bethesda,
MD).

Applicants should include a statement in their applications indicating
their willingness to participate in such meetings and to cooperate with
other researchers at other interdisciplinary research program sites.

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

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

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 January 6, 1995, 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
subsequent applications, the information that it contains is helpful in
planning for the review of applications.

The letter of intent is to be sent to:

Dr. C.James Scheirer,
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553 A
Bethesda, MD  20892

APPLICATION PROCEDURES

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

Applicants must follow the instructions provided in the RFA.  The RFA
label available in the PHS 398 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, to
identify the application as a response to this RFA, check "YES," enter
the title, "Etiology of Excess Cardiovascular Disease in Diabetes
Mellitus," and the RFA number HL-95-004 on Line 2a of the face page of
the application.

Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package
to:

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

Send two additional copies of the application to Dr. James Scheirer, at
the address listed under LETTER OF INTENT.  It is important to send
these two copies at the same time as the original and three copies are
sent to the Division of Research Grants, otherwise the NHLBI cannot
guarantee that the application will be reviewed in competition for this
RFA.

Applications must be received by April 11, 1995.  If an application is
received after that date, it will be returned to the applicant.  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, or 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.

Letter of Authorization

Applicants must submit a brief letter to the NHLBI indicating that they
will allow their applications to be considered for funding by the JDFI.
All materials relating to the application will be promptly forwarded to
the JDFI by NHLBI.  The summary statements for such applications will
be shared with the JDFI at the time of their availability.  Letters of
authorization should be prepared by the Principal Investigator and
co-signed by the official signing for the applicant institution.  This
letter may be combined with the LETTER OF INTENT or may be submitted
directly to Dr. Savage or Dr. Robinson at the address listed INQUIRIES.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG and
for responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
group convened by the NHLBI in accordance with the review criteria
stated below.  As part of the initial merit review, a process (triage)
may be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be notified.

Neither site visits nor reverse site visits are planned as a part of
the review process, therefore each application should be complete on
submission.  Following the initial review group consideration,
secondary review of applications will be conducted by the National
Heart, Lung and Blood Advisory Council and the Juvenile Diabetes
Foundation International Scientific Advisory Board.

The criteria for review of applications will be those used regularly
for the review of program project grant applications by the NHLBI.  A
complete and detailed description of these criteria is contained in
"Program Project Grant:  Preparation of the Application", NHLBI, US
DHHS, August 1992, a copy of which may be obtained from Dr Scheirer at
the address listed under LETTER OF INTENT.  Awardees will be selected
on the basis of the priority score of their individual applications,
subproject scores, and the ability of that proposal to contribute to a
comprehensive investigation of diabetic cardiovascular disease.

Review criteria for this RFA are generally the same as those for
unsolicited interdisciplinary research grant applications:

o  the scientific merit of each proposed project in the application,
including originality, feasibility of the approach, and adequacy of the
experimental design;

o  the integration of the clinical and fundamental research into a
coherent enterprise with adequate plans for interaction and
communication of information and concepts among the collaborating
investigators;

o  if applicable, the technical merit and justification of each core
unit;

o  the qualifications, experience, and commitment of the Program
Project Principal Investigator and his/her ability to devote adequate
time and effort to provide effective leadership;

o  the competence of the subproject investigators to accomplish the
proposed research goals, their commitment, and the time they will
devote to the program;

o  the adequacy of facilities to perform the proposed research
including the laboratory and clinical facilities, access to subjects,
instrumentation, and data management systems when needed;

o  the scientific and administrative structure of the program,
including adequate internal and external arrangements and procedures
for monitoring and evaluating the proposed research and for providing
ongoing quality control and scientific review;

o  the institutional commitment to the program and the appropriateness
of the institutional resources and policies for the administration of
a research program of the type proposed; and

o  the appropriateness of the budget for the proposed program.

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.

AWARD CRITERIA

Applications must fulfill all the eligibility and responsiveness
criteria in order to be considered for funding.  Since a variety of
approaches would represent valid responses to this RFA, it is
anticipated that there will be a range of costs among individual grants
awarded.  The most important criterion in selecting awardees will be
the scientific merit as reflected in the priority score.  However,
factors such as program balance and available funds may enter into
selection from among meritorious applications.

Application must be received by April 11, 1995.  An application not
received by this date will be considered ineligible.

Schedule

Letter of Intent Receipt Date:    January 6, 1995
Application Receipt Date:         April 11, 1995
Initial Review:                   June/July 1995
Review by NHLB Advisory Council:  September 1995
Review by JDFI Advisory Board:    September 1995
Anticipated Award Date:           September 30, 1995

INQUIRIES

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

Peter J. Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Federal Building, Room 300
7750 Wisconsin Avenue, MSC 9070
Bethesda, MD  20892-9070
Telephone:  (301) 496-4333
FAX:  (301) 480-5298
Email:  sav@cu.nih.gov

David M. Robinson, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 416
7750 Wisconsin Avenue, MSC 9070
Bethesda, MD  20892-9070
Telephone:  (301) 496-5656
FAX:  (301) 402-3508
Email:  drw@cu.nih.gov

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7458
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
number 93.387, Heart and Vascular Diseases. Awards are made under the
authority of the Public Health Service Act, Section 301 (42 USC 241)
and administered under PHS grants policies and Federal regulations,
most specifically 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372, or to Health Systems Agency Review.

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

.

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