Full Text HL-96-018
 
HOMOCYST(E)INEMIA AND ATHEROSCLEROSIS
 
NIH GUIDE, Volume 25, Number 25, July 26, 1996
 
RFA:  HL-96-018
 
P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Molecular Genetics 

 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  September 15, 1996
Application Receipt Date:  November 20, 1996
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE FULL
RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION
INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN
RESPONSE TO THIS RFA.
 
PURPOSE
 
The purpose of this solicitation is to promote research into the
precise mechanisms by which homocysteine induces arterial occlusive
disease as well as to investigate the role of hyperhomocyst(e)inemia
in the development of atherosclerotic lesions.  Additionally, this
solicitation will encourage the development of enzymatic assays and
molecular genetic diagnostic tests for cystathionine  - synthase,
methylenetetrahydrofolate reductase and methionine synthase in
homocyst(e)inemic individuals.
 
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 request
for applications (RFA), Homocyst(e)inemia and Atherosclerosis, is
related to the priority area of heart disease and stroke.  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
 
Applications may be submitted by domestic and foreign, for-profit and
nonprofit 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.
 
All current policies and requirements that govern the research grant
programs of the NIH will apply to grants awarded under this RFA.
Awards under this RFA to foreign institutions will be made only for
research of very unusual merit, need, and promise, and in accordance
with Public Health Service policy governing such awards.
 
Cell biology, molecular biology, biochemistry, physiology, pathology,
and genetics. are among the disciplines and expertise that may be
appropriate for this research program.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH individual research project grant (R01)
mechanism of support.  However, specific application instructions
have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME"
streamlining efforts being examined by the NIH.  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.
 
For this RFA, funds must be requested in $25,000 direct cost modules
and a maximum of seven modules ($175,000 direct costs) per year may
be requested.  A feature of the modular grant concept is that no
escalation is provided for future years, and all anticipated expenses
for all years of the project must be included within the number of
modules being requested.  Only limited budget information will be
required and any budget adjustments made by the Initial Review Group
will be in modules of $25,000.  Instructions for completing the
Biographical Sketch have also been modified.  In addition, Other
Support information and the application Checklist page are not
required as part of the initial application.  If there is a
possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following the
initial review.  The APPLICATION PROCEDURES section of this RFA
provides specific details of modifications to standard PHS 398
application kit instructions.
 
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.  It is anticipated that support for
this program will begin in July 1997.  Administrative adjustments in
project period and/or amount may be required at the time of the
award.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1997, approximately $1,500,000
total costs will be available for the first year of support for this
initiative.  Award of grants pursuant to this RFA is contingent upon
receipt of such funds for this purpose.  It is anticipated that
approximately six new grants will be awarded under this program.
Applicants may request up to four years of support.  The specific
number to be funded will, however, depend on the merit and scope of
the applications received and on the availability of funds.  Direct
costs will be awarded in modules of $25,000, less any overlap or
other necessary administrative adjustments.  Indirect costs will be
awarded based on the negotiated rates.
 
RESEARCH OBJECTIVES
 
Background
 
Atherosclerotic cardiovascular disease is a major cause of mortality
and morbidity in the United States.  Risk factors such as
hyperlipidemia, hypertension and cigarette smoking account for a high
proportion of cardiovascular deaths. However, some cases cannot be
explained by these conventional risk factors.  The presence of raised
levels of homocyst(e)ine may help explain these cases.
 
The interest in homocysteine and its relation to cardiovascular
disease was initially stimulated by the discovery of homocystinuria.
Homocystinuria due to a cystathionine beta-synthase (CBS) deficiency
is an autosomal recessive condition characterized by elevated plasma
concentrations of homocysteine in urine and blood and premature
arteriosclerosis.  CBS is the enzyme required for the conversion of
homocyst(e)ine to cystathionine.  Without this enzyme, homocyst(e)ine
builds up in the blood and in tissues.  Four organ systems show major
involvement: the eye, skeletal, central nervous, and vascular
systems. Homocystinuria is usually associated with serious
thromboembolic complications at an early age; thrombosis of
extracranial and intracranial arteries, veins and sinuses as well as
coronary occlusion are common fatal occurrences. For untreated
patients the risk of thromboembolism is approximately 25 percent by
the age of 15 years old.  Premature arteriosclerotic lesions in most
large and medium sized arteries are common in these patients.  The
lesions are composed of proliferating smooth muscle cells surrounded
by large amounts of collagen, elastic fibers, and glycosaminoglycans.
Fatty atheromatous plaques have only occasionally been observed in
homocystinuric patients. The frequency for CBS homozygosity in the
normal population is between 1 in 100,000 and 1 in 335,000 live
births whereas the frequency for heterozygosity is 1 in 200.
 
The normal concentration of homocysteine in plasma is about 10
nmol/ml.  In contrast, homocystinuric patients may attain
homocysteine concentration levels as high as 200-400 nmol/ml.
Patients with cardiovascular disease may have
"hyperhomocyst(e)inemia" or moderately elevated homocysteine (13-25
nmol/ml) levels.  Similar to the role of cholesterol in coronary
artery disease, homocysteine is a graded risk factor and vascular
risk rises with increasing homocysteine levels.  Depending upon the
cutoff level selected as indicating hyperhomocyst(e)inemia, 10 to 50
percent of patients with arteriosclerotic vascular disease have
"elevated" levels.
 
The determinants of moderately elevated levels of homocysteine are
not completely understood. Hyperhomocyst(e)inemia could be due to
dietary deficiencies such as folate, vitamin B6 and vitamin B12,
and/or due to genetic or acquired defects in the absorption and
utilization of these vitamins.  Genetic functional defects in various
enzymes involved in folic acid, methionine and Vitamin B12 metabolism
might account for other cases.
 
In the last five years there has been a growing body of literature
relating homocyst(e)inemia to vascular disease and indicating that
the relation is independent of other risk factors.  The most recent
studies have suggested that elevated plasma concentrations of
homocysteine are associated with coronary atherosclerosis and
thrombosis.
 
The frequency of putative heterozygosity for hyperhomocyst(e)inemia
among patients with clinical signs of ischemic disease was
investigated in 1985. Approximately 30 percent of the patients with
occlusive peripheral arterial and cerebrovascular disease had
homocysteine levels in heterozygote range.  Similar findings were
reported (1991) in a study involving l23 patients with vascular
disease. Hyperhomocyst(e)inemia was detected in 42 percent of
patients with cerebrovascular disease, in 30 percent of patients with
coronary vascular disease and in 28 percent of patients with
peripheral vascular disease but in none of the 27 normal subjects.
This study strongly suggested that hyperhomocyst(e)inemia was an
independent risk factor for vascular disease, including coronary
vascular disease.  Recently, a nested case-control study using
previously collected blood samples was published.  Samples from 271
physicians who subsequently developed myocardial infarction were
analyzed for homocyst(e)ine levels together with paired controls.
They found that men with homocyst(e)ine levels above 15.8 nmoles/ml
(95th percentile) had a three fold increased risk for myocardial
infarction compared with those in the bottom 95% of the control
distribution (<14.1 nmoles/ml).  However, only seven percent of the
cases was attributable to elevated levels of homocyst(e)ine.  It was
suggested that the reason the percentage was less than found in other
studies may reflect the better nutritional state of physicians over
the general population.  High vitamin intake was correlated with
lower homocyst(e)ine levels in the population.  By contrast,
individuals in the population with low normal folate levels may
develop hyperhomocyst(e)inemia and thus be at risk for thrombosis and
coronary disease.
 
Several hypotheses have been advanced to explain the mechanisms
involved in the pathology caused by homocysteine.  Homocysteine may
increase the adhesiveness of platelets which leads to increased
thrombogenesis or it may be toxic and cause endothelial injury.
Homocysteine has also been shown to stimulate the binding of Lp(a) to
fibrin.  This may decrease the fibrinolytic potential of the blood
vessel wall and promote thrombosis.  Furthermore, it has been
suggested that homocysteine may produce reactive oxygen species which
modify LDL to oxidized LDL, and thus accelerate the process of
atherogenesis.  However, no single mechanism has been definitively
shown to lead to the pathology associated with
hyperhomocyst(e)inemia.
 
The potential atherogenic properties of homocysteine have been
evaluated by both in vivo and in vitro experiments. Short term
injection of homocysteine caused patchy loss of arterial endothelium
in baboons.  In contrast, sustained treatment induced arterial
damages resembling those observed in early human arteriosclerosis.
Endothelial damage, platelet sequestration, and venous thrombosis
were also observed in rats given a single homocysteine injection.
Homocysteine also promotes detachment of human endothelial cells from
tissue culture dishes suggesting that homocysteine may contribute to
atherogenesis by diminishing cell adhesion.
 
The pathology of the vascular lesions has been mainly examined in
patients with the homocystinuria.  A notable pathological feature in
these patients is the intimal thickening and the presence of fibrous
plaques in the vessel walls. No lipid deposits have been observed in
the arterial lesions.  However, it should be pointed out that most of
these autopsy data come from young patients.  Additional
characterization of the pathology of vascular lesions in
hyperhomocyst(e)inemia would be helpful in the elucidation of the
mechanisms responsible for vascular diseases in these patients.
 
Choline-deficient rats, pyridoxine-deficient monkeys and pigs, and
homocysteine- injected rabbits have been used to study the
pathogenesis of arteriosclerosis associated with
hyperhomocyst(e)inemia.  But for unknown reasons the experimentally-
induced arteriosclerosis in these animal models cannot always be
reproduced. Recently, a CBS knockout mouse was developed and is being
used to study cellular and molecular mechanisms of
hyperhomocyst(e)inemia.  However, animal models are still needed in
which cellular and molecular mechanisms involved in the pathogenesis
of arterial damage associated with hyperhomocyst(e)inemia can be
tested.
 
There has been increasing interest in the genetic defects that cause
hyperhomocyst(e)inemia.  Recently, a mutation
inmethylenetetrahydrofolate reductase (MTHFR) has been identified.
This enzyme catalyzes the reduction of methylenetetrahydrofolate to
methyltetrahydrofolate, a cofactor for homocysteine methylation to
methionine. Since the identification of this mutation several (but
not all) studies have shown an association of this thermo-labile
MTHFR defect in homocysteine metabolism with premature coronary
disease.  Individuals homozygous for the mutation have elevated
plasma homocysteine levels.  Interestingly, 10-15% of the population
are homozygous, and thus may represent an important genetic risk
factor in vascular disease.
 
Methionine synthase (MS) is another important enzyme involved in
homocysteine metabolism.  MS is involved in the remethylation of
homocysteine to methionine.  However, the gene for MS has not been
cloned yet, and thus few studies have been done on this enzyme.
 
While techniques are available to measure homocyst(e)ine levels,
better molecular methods are needed to determine heterozygosity and
homozygosity for various CBS and MTHFR mutations.  The exact role of
mutations and polymorphisms of these and other enzymes (such as MS)
in various types of vascular disease, needs further definition.  At
the present time, heterozygosity for CBS deficiency, even though
claimed to be common in vascular disease by measurement of
homocysteine levels, could not be detected using more definitive
direct molecular testing.
 
Treatment of elevated levels of homocyst(e)ine is simple and
apparently innocuous.  Hyperhomocyst(e)inemia is readily treated with
folate (0.4 to 10mg), a vitamin that normalizes homocyst(e)ine
metabolism.  Folate seems to have a universal potential for reducing
fasting plasma levels of homocysteine regardless of etiology.  Other
therapies such as supplementation with B12 and B6 produce biochemical
and clinical improvement in patients who have elevated levels due to
B12 and B6 deficiencies.  Thus, hyperhomocyst(e)inemia is potentially
a treatable risk factor for vascular diseases.
 
It has not been proven, however, whether identification and treatment
of  hyperhomocyst(e)inemic subjects will reduce the risk of coronary
disease.  However, it is important to understand the mechanisms
involved in this disease as well as to develop the technology to
identify better those individuals with hyperhomocyst(e)inemia who may
be at risk.
 
Objectives
 
Many aspects of the relationship between homocysteine and vascular
diseases remain to be determined.  Studies are required to determine
the precise mechanisms by which homocysteine induces arterial
occlusive disease as well as to investigate the role of
hyperhomocyst(e)inemia in the development of atherosclerotic lesions.
Examples of topics that would be appropriate for this initiative are
given below.  This list is not to be regarded as complete or
exclusive, and other research areas proposed by applicants that meet
the objectives of this program will be considered by the NHLBI.
Active collaboration among molecular and cell biologists,
physiologists, pathologists, geneticists and biochemists are highly
encouraged.  Representative areas of research might include:
 
o  Investigation of the action of homocysteine on the fibrinolytic
and coagulation processes leading to atherosclerosis and/or
thromboembolism.  For example, homocysteine has been shown to
stimulate the binding of Lp(a) to plasmin-treated fibrin which may
contribute to the thrombotic disease seen in patients with
homocyst(e)inemia.  Homocysteine also enhances endothelial cell
factor V activity which initiates blood coagulation.
 
o  Investigation of the interaction of homocysteine with plasma
proteins.  For example, can homocysteine modify apo B100 or LDL and
promote its atherogenicity?  Protein-bound homocysteine accounts for
greater than 85% of total plasma homocyst(e)ine.  Homocysteine can
form mixed disulfide linkages with plasma proteins.  Albumin appears
to be a primary carrier, but other proteins may also interact with
homocysteine, particularly when there is excess production. The role
that "homocysteinylated" proteins might play in atherogenesis is
unknown.
 
o  Examination and characterization of the vascular lesions in
hyperhomocyst(e)inemia.  There are no studies that have examined the
vascular lesions found in hyperhomocyst(e)inemic individuals, and
tried to correlate the severity of the lesion with the levels of
homocysteine.
 
o  Development of animal models in which the cellular and molecular
mechanisms involved in the pathogenesis of arterial damage associated
with homocyst(e)inemia could be tested.  Present models that are
produced through chemical modifications do not give consistent
results.  Thus far only one animal model, CBS knockout mouse, has
been produced which could be used to study cellular and molecular
mechanisms.
 
o  Investigation of the molecular genetics of CBS, MTHFR and MS
deficiencies.  The human gene has been cloned for the CBS and MTHFR
deficiencies, and mutations in these genes can now be identified
using established molecular techniques.  The gene has not yet been
cloned for the MS deficiency.  Further molecular studies on these and
related genes and their respective enzymes, with attention to
diagnostic screening, would be desirable.
 
o  Investigation of homocysteine metabolism in humans. Little is
known about homocysteine metabolism in cardiovascular cells and
tissues.  For example, rat heart has little or no detectable CBS
activity, but what is the situation in human cardiovascular tissues?
Cells unable to metabolize homocysteine by the transsulfuration
pathway may be particularly sensitive to increased plasma levels seen
in hyperhomocyst(e)inemia.
 
o  Investigation of the short term effects of homocyst(e)ine on
vascular tone and vascular reactivity.
 
o  Investigation of the primary and secondary causes of
hyperhomocyst(e)inemia in homocyst(e)inemic patients with
atherosclerosis and cardiovascular diseases.
 
This initiative will not support grants that focus on large
epidemiological studies or clinical trials.  In addition, any
application that focuses on cerebrovascular  disease or stroke should
be addressed to the National Institute of Neurological Disorders and
Stroke.
 
SPECIAL REQUIREMENTS
 
Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program.  In the budget for the grant
application, applicants should request travel funds for a one day
meeting each year, most likely to be held in Bethesda, Maryland.
Applicants should also include a statement in their applications
indicating their willingness to participate in these meetings.
 
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), that
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 to 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 September 15, 1996, 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
staff to estimate the potential review workload and to avoid conflict
of interest in the review.
 
The letter of intent is to be sent to:
 
Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  James_Scheirer@NIH.GOV
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants, with the modifications noted below.
Applications kits are available at most institutional offices of
sponsored research and may be obtained from the Grants Information
Office, Office 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@odrockm1.od.nih.gov; and from the program administrator listed
under INQUIRIES.
 
The RFA label found 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, 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.
 
Sample budgets and justification page will be provided upon request
or following the submission of a letter of intent.
 
BUDGET INSTRUCTIONS
 
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:
 
o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete
Form Page 4 of the PHS 398 (rev 5/95).  It is not required nor will
it be accepted at the time of application.
 
o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete
the categorical budget tables on Form page 5 of the PHS 398 (rev.
5/95).  Only the requested total direct costs line for each year must
be completed based on the number of $25,000 modules being requested.
Applicants may not request a change in the amount of each module.  A
maximum of seven modules ($175,000 direct costs) per year may be
requested and each applicant may request up to four years of support
for this RFA.  Direct cost budgets will remain constant throughout
the life of the project (i.e., the same number of modules requested
for all budget periods).  Any necessary escalation should be
considered when determining the number of modules to be requested.
However, in the event that the number of modules requested must
change in any future year due to the nature of the research proposed,
appropriate justification must be provided.  Total Direct Costs for
the Entire Proposed Project Period should be shown in the box
provided.
 
BUDGET JUSTIFICATION
 
- Budget justifications should be provided under "Justifications" on
Form Page 5 of the PHS 398.
 
- List the names, role on the project and proposed percent effort for
all project personnel (salaried or unsalaried)and provide a narrative
justification for each person based on his/her role on the project.
 
- Identify all consultants by name and organizational affiliation and
describe the services to be performed.
 
- Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.
More detailed justifications should be provided for high cost items.
Any large one-time purchases, such as large equipment requests, must
be accommodated within these limits.
 
CONSORTIUM/CONTRACTUAL COSTS
 
If collaborations or subcontracts are involved that require transfer
of funds from the grantee to other institutions, it is necessary to
establish formal subcontract agreements with each collaborating
institution.  A letter of intent from each collaborating institution
should be submitted with the application.  Only the percentage of the
consortium/contractual TOTAL COSTS (direct and indirect) relative to
the total DIRECT COSTS of the overall project needs to be stated at
this time. The following example should be used to indicate the
percentage cost of the consortium, "The consortium agreement
represents 27% of overall $175,000 direct costs requested in the
first year.". A budget justification for the consortium should be
provided as described in the "Budget Justification" section above (no
Form Page 5 required for the consortium).  Please indicate whether
the consortium will be in place for the entire project period and
identify any future year changes in the percentage relative to the
parent grant.
 
If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all years
of the consortium.  Please note that total subcontract costs need not
be calculated in $25,000 modules. However, when subcontract funds are
added to the parent grant budget, the total direct cost amount must
be included in the number of $25,000 modules requested.
 
BIOGRAPHICAL SKETCH
 
A biographical sketch is required for all key personnel, following
the modified instructions below.  Do not exceed the two-page limit
for each person.
 
- Complete the educational block at the top of the form page;
 
- List current position(s) and those previous positions directly
relevant to the application;
 
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
 
- The applicant has the option to provide information on research
projects completed and/or research grants participated in during the
last five years that are relevant to the proposed project.
 
OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page
7).  Selected other support information relevant to the proposed
research may be included in the Biographical Sketch as indicated
above.  Complete Other Support information will be requested by NHLBI
staff if there is a possibility for an award.
 
CHECKLIST
 
No "Checklist" page is required as part of the initial application.
A completed Checklist will be requested by NHLBI staff if there is a
possibility for an award.
 
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.
 
Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further review.
 
Submit a signed, typewritten original of the application and 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 the time of submission, two additional copies of the application
must be sent to Dr. C. James Scheirer, at the same address listed
under LETTER OF INTENT.
 
Applications must be received by November 20, 1996.  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 already reviewed, but such applications
must include an introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened 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, generally
the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
National Heart, Lung, and Blood Advisory Council.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims.  Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.
 
Other review criteria will include:
 
o  scientific, technical or medical significance and originality of
proposed research
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research
 
o  availability of the resources necessary to perform the research
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.
 
Schedule
 
Letter of Intent Receipt Date:     September 15, 1996
Application Receipt Date:          November 20, 1996
Initial Review:                    February/March 1997
Review by NHLBI Advisory Council:  May 1997
Anticipated Award Date:            July 1, 1997
 
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 and requests for
sample budget pages to:
 
Sonia Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 10186
6701 Rockledge Drive
Bethesda, MD  20892-7956
Telephone:  (301)435-0550
FAX:  (301) 480-2848
Email:  SKARLATS@GWGATE.NHLBI.NIH.GOV
 
Direct inquiries regarding fiscal matters to:
 
Mr. William Darby
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 7128
6701 Rockledge Drive
Bethesda, MD  20892-7128
Telephone:  (301)435-0177
FAX:  (301)480-3310
Email:  William_Darby@NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.837.  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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