CELLULAR AND MOLECULAR MECHANISMS OF DIABETIC CARDIOMYOPATHY

Release Date:  January 18, 2000

RFA:  HL-00-009

National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Aging

Letter of Intent Receipt Date:  March 3, 2000
Application Receipt Date:       April 21, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES  
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN  RESPONSE TO THIS RFA.

PURPOSE

The objective of this initiative is to support research to elucidate the 
cellular and molecular mechanisms that underlie the pathogenic processes 
occurring in the heart leading to diabetic cardiomyopathy.  The overall goal 
is to stimulate  innovative multidisciplinary research to develop new 
strategies that effectively prevent or treat cardiac myopathic disease 
progression  in diabetic patients. 


HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA),  
CELLULAR AND MOLECULAR MECHANISMS OF DIABETIC CARDIOMYOPATHY is related to one 
or more of the priority areas.  Potential applicants may obtain a copy of 
"Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government. Racial/ethnic minority individuals, women, 
and persons with disabilities are encouraged to apply as Principal 
Investigators.



MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 4 years.  This RFA is 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.  The anticipated award date is September 29, 2000.

FUNDS AVAILABLE

For FY 2000, the NHLBI intends to commit approximately $4,000,000  and the 
NIDDK and NIA intend to commit approximately $250,000 and $500,000, 
respectively to fund 12 to 16  new grants in response to this RFA. An 
applicant may request a project period of up to 4 years and a budget for 
direct costs for up to 10 modules of $25,000 each (maximum $250,000 direct 
costs) per year, including Facilities and Administrative Costs on consortium 
arrangements.  Because the nature and scope of the research proposed may vary, 
it is anticipated that the size of each award will also vary. Although the 
financial plans of the NHLBI, NIDDK and NIA provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications.  At this time, 
it is not known if competing renewal applications will be accepted and/or if 
this RFA will be reissued.

RESEARCH OBJECTIVES

Background

Cardiovascular disease represents the major cause of morbidity and mortality 
in diabetic patients.  Patients with diabetes also have fewer warning signs of 
heart attack, increased mortality during the first year after a heart attack, 
poorer response to angioplasty, and higher rates of congestive heart failure. 
 Increased risks for heart failure and death in patients with diabetes 
mellitus are especially pronounced in women, African-Americans, certain Native 
Americans and the elderly.  One reason for the poor prognosis in patients with 
both diabetes and ischemic heart disease seems to be an worsened myocardial 
function leading to accelerated heart failure (diabetic cardiomyopathy).  
Despite the obvious importance of diabetic cardiomyopathy, a better 
understanding of this complex and very likely multi-factorial problem at the 
cellular and molecular levels is lacking.  Also, there has been very little 
progress in understanding its underlying pathophysiology, specific 
manifestations and natural history in patients, and treatment.  


Prior to 1972, the increased cardiovascular morbidity and mortality that 
diabetics endure had been attributed to vascular disease.  In 1972,  Rubler et 
al. first described a specific type of cardiomyopathy related to diabetes, 
suggesting that this myocardial disease exists as an independent clinical 
entity.  The term "diabetic cardiomyopathy" was proposed.  This work has 
subsequently been followed by numerous investigations reporting cardiac 
dysfunction in diabetic patients which occurred in either the absence or 
presence of coronary artery disease.  Diabetic cardiomyopathy, as an early 
complication of diabetes,  is manifested by diastolic dysfunction  followed by 
abnormalities in systolic function. When presenting with other cardiovascular 
complications (i.e., ischemic heart disease or hypertension), diabetic 
patients have a much worse prognosis than non-diabetic patients and are more 
prone to progress to congestive heart failure . The underlying diabetic 
cardiomyopathy appears to contribute to accelerated heart failure. 

Although several mechanisms have been proposed for diabetic cardiomyopathy,  
the pathogenesis of this disease is unknown.  Common histopathologic 
abnormalities of diabetic cardiomyopathy include small vessel disease, 
interstitial fibrosis and myocardial hypertrophy.  However, there is 
conflicting evidence regarding the relative role of these derangements in the 
development of diabetic cardiomyopathy.   Also unsettled is the relationship 
of these cardiac changes to the type of diabetes, its duration and its 
severity.  Much of what is known about the pathogenesis of diabetic 
complications has been gleaned from studies using animal models.  By far the 
most extensively employed animal model is the streptozotocin (STZ)-induced 
diabetes mellitus in the rat.  Rats given STZ for weeks to months develop 
hypoinsulinemic diabetes mellitus, with consistent depression of myocardial 
contraction, and, most especially, relaxation.  Effects on "passive" diastolic 
compliance have been variable.  These contractile abnormalities are correlated 
with several alterations in excitation-contraction coupling, ion transport and 
exchange, including prolongation of the action potential, and depressed 
sarcoplasmic reticular calcium pumping and sarcolemmal Na/Ca exchange.  
Abnormalities of the contractile machinery have also been detected in 
mechanical studies in skinned strips, in addition to a V1 to V3 isomyosin 
switch.  While the STZ-diabetes mellitus rat is a reliable, well-characterized 
model, it may not be the most relevant model for human disease, particularly 
Type II diabetes.

Clinical and experimental studies have provided only limited insights into the 
mechanism(s) of diabetic cardiomyopathy.  Free radical production with altered 
lipid content of membranes is one postulated mechanism.  The direct effects of 
abnormal carbohydrate metabolism and excessive fatty acid oxidation have been 
implicated as an important proximate cause of diabetic cardiomyopathy in STZ 
treated rats.  However, several other consequences of abnormal carbohydrate 
metabolism, for example, depressed pyruvate dehydrogenase activity and 
inadequate energy availability, have also been proposed to account for 
diabetic cardiomyopathy.  Possible molecular/genetic mechanisms involved in 
diabetic cardiomyopathy in animal models have in general not been well 
characterized.   Microvascular disease and protein glycation/glycosylation, 
important mechanisms of complications in patients with diabetes mellitus, do 
not have particularly good counterparts in experimental models.  The direct 
effects of hyperglycemia are also difficult to characterize in intact animals. 
 Thus, the roles of these major components of diabetes mellitus in causation 
of diabetic cardiomyopathy are particularly difficult to evaluate. 


There has been little progress in characterizing the cellular and molecular 
features of diabetic cardiomyopathy in patients, much less their mechanisms.  
 It remains unclear whether there are differences between insulin dependent 
and non-insulin dependent forms of diabetes mellitus with respect to the 
development of diabetic cardiomyopathy.  Defining cardiac changes in diabetic 
humans is obviously extremely important in light of the fact that diabetes is 
a chronic disease  not well represented by animal models.

Proposed Research

This initiative is directed at elucidation of processes influencing  diabetic 
cardiomyopathy  at the molecular, cellular, tissue, and organ levels.  Studies 
focusing  on cellular and molecular mechanisms, genetic susceptibility, 
pharmacologic  intervention, and development of novel  strategies to treat and 
prevent progression of diabetic cardiomyopathy are sought.  The following aims 
are examples of the scope of the solicitation.  They are not exclusive and 
other innovative approaches are encouraged based on the applicant=s expertise 
and knowledge.

o  Develop and utilize experimental models with high relevance to human 
diabetic cardiomyopathy to answer specific, mechanistic questions 

o  Delineate connections between altered intracellular signaling, including 
those related to glucose transport and protein kinase C activation, and 
altered contractile function and cell death in disease states

o  Examine the relation between altered energy metabolism and myocardial 
function in diabetes mellitus

o  Elucidate the mechanisms contributing to the modification of cardiac 
responses to ischemia-reperfusion and oxidative stress in diabetes mellitus. 

o  Elucidate  myocardial cellular/molecular alterations in patients with 
diabetes mellitus.

o  Apply noninvasive imaging technologies to define alterations in the 
myocardium of diabetic patients

o  Examine the fundamental reasons for gender, racial and ethnic variations in 
diabetes mellitus associated cardiomyopathy. 

o  Develop novel therapeutic interventions using innovative genetic, molecular 
and cellular approaches


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 policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

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

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

LETTER OF INTENT

Prospective applicants are asked to submit 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 NHLBI, NIDDK 
and NIA staff to estimate the potential review workload and avoid conflict of 
interest in the review.

The letter of intent is to be mailed, or faxed, by March 3, 2000 to: 

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541
Email: js110j@nih.gov.

APPLICATION PROCEDURES


Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and  detailed instructions and information on Modular Grant 
applications can be found at  
http://grants.nih.gov/grants/funding/modular/modular.htm

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label. 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 of the face page of the application for and the YES box 
must be marked.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has 
been modified to allow for this change.  Please note this is in pdf format.

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

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

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

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301)435-0266
FAX: (301)480-3541
Email: js110j@nih.gov.


Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.  

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.

BUDGET INSTRUCTIONS

Modular Grant applications  will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. The total direct costs 
must be requested  in accordance with the  program guidelines and  the 
modifications made to the standard  PHS 398 application  instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative  (F&A) costs] for the initial budget 
period Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
 salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000. List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of key personnel, and the role 
on the project. Indicate whether the collaborating institution is foreign or 
domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.


Provide an additional narrative budget justification for any variation in 
subsequent years in the number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for all 
key personnel, following the instructions below. No more than three pages may 
be used for each person. A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied  in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI, NIDDK and NIA.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the NHLBI and NIDDK and NIA National Advisory Councils.

Review Criteria


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

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

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

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

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

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

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

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.


Schedule

Letter of Intent Receipt Date:    March 3, 2000
Application Receipt Date:         April 21, 2000
Peer Review Date:                 June/July 2000
Council Review:                   September 7-8, 2000
Earliest Anticipated Start Date:  September 29, 2000

AWARD CRITERIA

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

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Isabella Liang, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 9142
6701 Rockledge Drive
Bethesda, MD  20892-7940
Telephone:  (301)435-0520
FAX:  (301) 480-1335
Email: liangi@nih.gov

Barbara Linder, M.D., Ph.D.
Division of Diabetes. Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN18A
Bethesda, MD 20892
Telephone: (301) 594-0021
FAX: (301) 480-3503
Email: linderb@extra.niddk.nih.gov

David B. Finkelstein, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD  20892
Telephone:  (301) 496-6402
FAX:  (301) 480-0010
Email: finkelsd@nia.nih.gov

Direct inquiries regarding fiscal matters to:

Ms.  Carol Dangel
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 7140

6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301)435-0177
FAX:  (301)480-3310
Email: dangelc@nih.gov

Ms. Charlette Kenley
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AS49D
Bethesda, MD 20892
Telephone: (301) 594-8847
FAX: (301) 480-3504
Email: kenleyc@extra.niddk.nih.gov

Ms. Crystal Ferguson
Grants and Contract Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: fergusoc@nia.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.837, 93.847 and 93.866.  Awards are made under authorization of Sections 
301 and  405 of the Public Health Service Act, as amended (42 USC 241 and 284) 
and administered under NIH grants policies and Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

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


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