kristoff@GENBANK.BIO.NET (Dave Kristofferson) (11/10/90)
ALZHEIMER'S DISEASE CENTER CORE GRANTS
RFA AVAILABLE: AG-91-02
P.T. 04; K.W. 0715180, 0710010, 0715138
National Institute on Aging
Letter of Intent Receipt Date: December 3, 1990
Application Receipt Date: February 11, 1991
BACKGROUND
The National Institute on Aging (NIA) is inviting
applications from qualified institutions for Alzheimer's
Disease Center Core grants (ADCC), which are designed to
serve as shared research resources to facilitate research in
Alzheimer's disease (AD). The NIA currently supports five
ADCCs. This one-time solicitation is designed to increase
the number of ADCCs. The NIA Alzheimer's Disease Centers
program is authorized by the Public Health Service Act,
Section 445, and includes 15 Alzheimer's Disease Research
Centers (ADRC) and the five ADCCs.
The ADRC program was designed to support multi-disciplinary
research on AD including clinical and other core resources,
basic and clinical research, and information and education
activities. Expansion of the program of the ADCCs will
complement the program of ADRCs and will enhance the capacity
of the institutions to conduct basic and clinical research in
AD by increasing the available research resources.
An ADCC will provide support for cores, which are shared
resources, to be utilized by ongoing and to-be-developed
scientifically meritorious research projects. An ADCC is
required to have an administrative, clinical,
neuropathological, and education and information transfer
core. Additional cores can be proposed. Each ADCC will fund
two pilot research projects per year through the
administrative core. The ADCCs will provide well-
characterized patients, patient and family information, and
tissue and biological samples for use in research projects.
Research proposals that will use ADCC core resources will be
supported through the usual NIH and other federal and non-
federal mechanisms for the funding of investigator-initiated
applications.
ELIGIBILITY
Institutions eligible for Center Core Grants (P30s) are those
at which there are (1) at least three prinicipal
investigators with any PHS agency grant or comparable peer
reviewed research project (including those funded by State
governments or private foundations) related to Alzheimer's
disease, each with at least two years of committed support
remaining at the time of application or (2) one or more
program projects (P01) grants related to AD, which also have
at least two years of committed support remaining.
Institutions that can demonstrate the ability to launch such
a research effort are also eligible.
MECHANISM OF SUPPORT
The support mechanism for this program will be the Center
Core Grant. Investigators may request up to five years of
support. The award of grants pursuant to this Request for
Applications (RFA) is
contingent upon the availability of funds for this purpose.
The intent is to fund up to five ADCC grants in Fiscal Year
1991. The specific number will depend upon the merit of the
applications received. These applications are not expected
to compete for funding within the general pool of dollars
available for investigator-initiated research proposals.
The total costs for each ADCC are limited to $600,000 for the
first year. Direct cost requests for subsequent years may
increase above the prior year direct cost award no more than
the standard NIH inflation factor.
While no future funds are set-aside, awards made in response
to this RFA may be renewed through the submission of a
competitive continuation application.
REVIEW CRITERIA
Applications received in response to the RFA will be reviewed
for scientific and technical merit by an NIA initial review
group. The factors to be considered in evaluating the merit
of each application will be those used in the review of the
cores in multiproject research grant applications. A core is
justified primarily on the basis of (1) the degree to which
its resources will be utilized by and benefit individual
ongoing funded projects and investigators and (2) the likely
impact of the core in fostering new meritorious research
projects. In addition, applicants should clearly demonstrate
the ways in which the ADCC will build the local research
program, will support ongoing projects, and will attract both
senior and new investigators to AD research.
REVIEW PROCEDURES
Proposals judged by staff to be non-responsive to the RFA
will be administratively withdrawn and returned to the
applicant without review. Responsive proposals may first
receive a preliminary review by a subcommittee of the review
panel to establish those applications deemed to be
competitive. Those judged noncompetitive will be so
designated, and an abbreviated summary statement noting the
major areas of concern will be sent to the principal
investigator. Applications judged to be competitive will be
given full review. Following review by the initial review
group, the applications will be considered by the National
Advisory Council on Aging.
All proposals should be complete in themselves. It is
unlikely that site visits will be conducted, therefore, each
application should be prepared as if no such visit will
occur.
In preparing proposals, applicants should follow the
instructions for PHS Form 398 and the specific supplemental
instructions available from NIA program staff. All human and
animal welfare assurances must be complete for a proposal to
be reviewed. All follow-up assurances and approval for
protocols submitted as pending must be received within 60
days of the application receipt deadline or earlier if
requested by the Executive Secretary. It is incumbent upon
the applicant to ensure that the Executive Secretary receives
all clearances by the established deadline or the application
will not be reviewed.
NIH requires applicants for grants to give added attention
(where feasible and appropriate) to the inclusion of women
and minorities in study populations and as units of analysis.
If minorities and women are not included in a study
population, a clear and convincing rationale for their
exclusion must be provided.
METHOD OF APPLYING
The application must be submitted on the 10/88 revision of
the form PHS 398. Supplemental instructions for preparing
ADCC proposals are available from the address below. To
identify these applications as being in response to the RFA,
check "yes" on item 2 of page 1 of the application and enter
the title: "ALZHEIMER'S DISEASE CENTER CORE GRANT" and the
RFA number. The RFA label available in the 10/88 revision of
the Application Form 398 must be affixed to the bottom of the
face page. 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.
Although not a prerequisite for applying, potential
applicants are encouraged to submit to the Chief, Dementias
of Aging, Neuroscience and Neuropsychology of Aging Program
(NNA), at the address indicated below, a non-binding letter
of intent to apply by December 3, l990.
The letter of intent should include a brief descriptive title,
the names of the principal investigator(s) and other key
investigators, and any other participating institutions.
The letter of intent
is not mandatory and does not influence review or
funding decisions, but it will enable the NIA to plan the
review, and will ensure that each potential applicant
receives relevant program information prior to expending
considerable effort in application preparation. Applications
must be received by February 11, 1991 for an earliest start
date of September 30, l991. If received late, the
application will be returned without review.
Applicants are strongly encouraged to obtain supplemental
information and to discuss their plans with and direct any
other inquirires to:
Chief, Dementias of Aging
NNA, NIA, NIH
Building 31, Room 5C35
9000 Rockville Pike
Bethesda, MD 20892
Telephone: (301) 496-9350
FAX: (301) 496-1494
Application kits may be secured from institutional offices of
grants and contracts or from:
Office of Grants Inquiries
DRG, NIH
Westwood Building, Room 449
5333 Westbard Avenue
Bethesda, MD 20892
Mail the complete application and four copies to:
DRG, NIH
Westwood Building, Room 240
Bethesda, MD 20892**
To expedite review, two exact copies should be sent to:
Chief, SRO, OEA, NIA, NIH
Building 31, Room 5C12
9000 Rockville Pike
Bethesda, MD 20892
COLLABORATIVE RESEARCH PLANNING GRANT - DIABETES
IN AMERICAN INDIANS AND ALASKA NATIVES
RFA NUMBER: DK-91-01
P.T. 34, FE; K.W. 0715075, 0755030, 0765033, 0745070, 0745027
National Institute of Diabetes and Digestive and Kidney
Diseases
Letter of Intent Receipt Date: December 15, 1990
Application Receipt Date: February 15, 1991
PURPOSE, SCOPE AND OBJECTIVE
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) and the Indian Health Service (IHS) have
initiated a joint program on Diabetes in American Indians
and Alaska Natives to help improve the health status of
these populations. In this Request for Applications (RFA),
NIDDK invites applications
for Collaborative Research Planning Grants to support the
development of plans for collaborative research projects
that address critical questions related specifically to the
etiology, pathogenesis, diagnosis, treatment, cure, and
prevention of diabetes mellitus and its complications in
American Indians and Alaska Natives.
DISCIPLINES AND EXPERTISE
Collaborative research studies proposed in response to this
RFA may involve basic biomedical research, clinical
research, behavioral research, education research, clinical
trials, and epidemiologic research. Accordingly, the
applicant research team should include individuals with the
appropriate scientific, medical, and sociocultural expertise
to pursue the proposed research project. In this regard,
special consideration should be given to including team
members with demonstrated access, knowledge, and cultural
sensitivity to the specified study population.
GENERAL BACKGROUND
The Report of the Secretary of Health and Human Services
Task Force on Black and Minority Health (1) identified
noninsulin-dependent diabetes (NIDDM) and its complications
as major public health problems in several minority
populations, including American Indians. Diabetes and its
complications have become an increasingly important health
problem for certain American Indian populations. Rates of
NIDDM are often 2-5 times higher among American Indians than
among other populations in the U.S. The incidence of
diabetes in the Pima Indians of Arizona is 19 times greater
than in Caucasians in Rochester, Minnesota, and the
difference continues to increase with time. With respect to
complications, diabetic end-stage renal disease (ESRD) is
more than five times more common in American Indians than in
the U.S. White population. Heart disease is the leading
cause of death in the Indian community and diabetes is a
major risk factor. Currently 4.1 percent of all births at
IHS facilities are complicated by diabetes. In addition,
mortality associated with diabetes in American Indians is
almost three times greater than for the U.S. as a whole.
In the United States, approximately half of the people with
NIDDM do not know they have the disease, and the proportion
of American Indians and Alaska Natives with unrecognized
NIDDM is unknown. Among American Indians and Alaska
Natives, as in other populations, the symptoms of NIDDM can
be very subtle and remain undetected for a long time. When
diagnosed, NIDDM is usually treated with diet and exercise
to control blood glucose levels. Oral hypoglycemic agents
or insulin injections are employed if necessary. A variety
of other interventions is also employed to help prevent or
delay the chronic complications of diabetes that affect
organs and tissues throughout the body.
SCIENTIFIC BACKGROUND
The NIDDK and IHS cosponsored a conference entitled Diabetes
in American Indians and Alaska Natives to review the state
of the art of science and to assess related progress, needs,
and opportunities for future research. Although the precise
reasons for the disproportionate prevalence, morbidity, and
mortality associated with NIDDM in American Indians and
Alaska Natives are still unknown, the results of research
studies suggest that the fundamental disease process
involved is essentially the same in both American Indian and
Caucasian populations. American Indians may differ,
however, in the nature and level of risk factors--genetic,
metabolic, and environmental--for NIDDM. For instance, it is
well established that obesity is a major risk factor for
NIDDM, and certain Indian populations have a much higher
prevalence of obesity than the majority of the U.S.
population.
Americans Indians have undergone rapid cultural changes
during this century, with many changes having taken place
during the last 40 to 50 years. Currently, the amount of
cultural and genetic admixture of American Indians with the
remaining U.S. population varies substantially. Far more
integration has occurred in some areas and some native
populations than in others (2). These changes may account
for part of the apparent tribal and geographic variation in
reported diabetes rates. A frequently overlooked, but
potentially important distinction, is the interplay of the
genetic, cultural, and historical heterogeneity of the
American Indian population. Tribal groups now living within
U.S. borders originated from several distinct migrations
from Asia into North America over a 40,000-year period.
Distinct subgroups of American Indians of different origin
can be identified by cultural descriptions, linguistic
analyses, and determination of genetic markers (3).
Multiple factors may contribute to current levels of risk
for diabetes in American Indians. Variations may exist
among tribal groups, secondary to genetic admixture, to both
the degree and duration of acculturation, and to attained
socioeconomic status. Therefore, it is important to
recognize that generalization about risk factors for
diabetes and its complications in American Indians may be
inappropriate and that extant data may only be valid in
groups with similar origins and history. Many studies have
been conducted only on individual tribes and have never been
repeated; therefore, data on temporal trends in diabetes
incidence, prevalence, and morbidity in American Indians and
Alaska Natives are limited.
MECHANISM OF SUPPORT
This RFA is a one-time solicitation by NIDDK for
applications for Collaborative Research Planning Grants
(R21) to help support the unique short-term needs of
investigators planning research studies related to diabetes
in American Indians and Alaska Natives. It is anticipated
that five to ten Collaborative Research Planning Grant
Awards will be made in response to this solicitation,
contingent on the receipt of meritorious applications and
the actual availability of appropriated funds. The award of
these Collaborative Research Planning Grants will be
followed within approximately one year by an RFA for
investigator-initiated research project grant applications
(RO1) related to this same program area. This subsequent
RFA will provide the opportunity for investigators to
establish support for periods up to five years for
meritorious research projects that address critical
questions related specifically to the etiology,
pathogenesis, diagnosis, treatment, cure, and prevention of
diabetes and its complications in American Indians and
Alaska Natives.
PROVISIONS OF THE AWARD
Approved Collaborative Research Planning Grant applications
should request no more than one year of funding for up to
$25,000 direct costs. Examples of the allowed uses of these
funds include: paying travel expenses of scientists,
clinicians, epidemiologists, tribal representatives, and
other essential personnel who will assist in the preparation
of the collaborative research plan; supporting retrieval and
analysis of extant data; supporting preliminary studies to
refine procedures, document recruitment potential, etc;
paying for secretarial assistance, telephone, postage, and
office supplies. In addition, the study team should also
have access to individuals with appropriate expertise in
statistics and data management, and consultant fees may be
paid for biostatisticians and epidemiologists (but not
generally for other personnel). Applicants should also
budget funds for the Principal Investigator and up to two
co-investigators to attend a two-day workshop in Phoenix,
Arizona, in November/December 1991. At that time,
recipients of Collaborative Research Planning Grants will be
invited to present their preliminary research proposals and
to participate with NIDDK and IHS staff in discussions
regarding specific problems, needs, and opportunities
related to both research and health care delivery.
SPECIAL REQUIREMENTS
A. The research team, composed of the Principal
Investigator, Co-Investigator(s), and/or collaborators must
include individual(s) who are experienced in health science
research. Involvement of individuals who have demonstrated
experience working with or delivering health services to
American Indian populations is highly desirable. The
application should include a succinct discussion of previous
relevant investigational and health care activities.
Letters of collaboration should be included for all proposed
consultants.
B. The applicant must demonstrate that the research team
has an understanding of, and is sensitive to, the target
population. Where specific language or cultural barriers
are important, the applicant must provide a plan for
addressing these barriers. The applicant must also document
that all affected tribes have been consulted. Letters must
be provided from the tribal leadership to document that they
have agreed to participate in the proposed research planning
process.
C. Since evidence exists of geographic variation in
diabetes rates and risk-factor levels among American Indians
and Alaska Natives, NIDDK staff may take into account
demographic and geographic distribution of peer reviewed and
approved applications in the final selection process in
order to support the development of research projects
involving an appropriate distribution of populations from
different geographic locations and linguistic groups.
ELIGIBILITY REQUIREMENTS
Applicants may be non-profit or for-profit organizations.
Teams of applicants are encouraged which could include
universities, public health departments, IHS hospitals,
voluntary organizations, health clinics, and federally
recognized Indian tribe or tribal organizations as defined
in P.L. 93-638 and amended by P.L. 100-472, etc., or
combinations thereof. Among a team of applicants, one
institution must be proposed as the lead organization to
serve as the Grantee Institution and assume responsibility
for the fiscal and programmatic conduct of the project.
Other members of the team should be proposed based on
individual consortium agreements (subcontracts) with those
organizations. The grantee organization and any proposed
consortium must have the staff and facilities required for
the proposed program.
REVIEW PROCEDURE
Applications received by February 15, 1991, will be reviewed
initially by the Division of Research Grants (DRG) for
completeness. Incomplete applications will be returned to
the applicant without further consideration. Evaluation for
responsiveness to the program requirements and criteria
stated in the RFA will be conducted by NIDDK program staff.
Applications that are judged non-responsive will also be
returned.
Those applications judged to be responsive will be further
evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review
group convened by the Division of Extramural Activities,
NIDDK, in consultation with the Indian Health Service
Research Program. Subsequently, a second level of review
will be performed by staff of the National Institute of
Diabetes and Digestive and Kidney Diseases to consider the
special needs and priorities of the Institute. Applications
recommended for approval will be considered for funding
beginning July 1, 1991.
REVIEW CRITERIA
Applicants are encouraged to submit and describe their own
ideas on how best to meet the objective of this RFA.
Applications will be judged primarily on (1) the likelihood
that the new knowledge that may be gained will subsequently
help to reduce the burden of diabetes and its complications
on the health status of American Indians and Alaska Natives;
(2) the potential scientific and technical merit of the
proposed project including the significance of the
scientific question(s), rationale, appropriateness of the
proposed planning process, consideration of appropriate
ethical issues, and availability of preliminary data; (3)
the agreement of a suitable American Indian population to
participate in planning the proposed study, and potential to
establish collaboration with the tribal groups and other
agencies involved in health care of the selected
populations; and (4) the qualifications and experience of
the proposed investigators.
Applicants are strongly encouraged to note these criteria
and to include sufficient information in their Collaborative
Research Planning Grant Application so that these aspects of
their proposal can be adequately assessed.
The review group will also critically examine the requested
budget and will recommend an appropriate budget and period
of support for each approved application.
Applicants are reminded of the NIH policy regarding the
inclusion of women in clinical research. For
further information, consult the NIH Guide for Grants and
Contracts, August 24, 1990, (Vol. 19, No. 31, pp. 18-19).
LETTER OF INTENT
Prospective applicants are requested to submit a letter of
intent by December 15, 1990, that includes a descriptive
title of the proposed research, the name, telephone number
and mailing address of the Principal Investigator, the names
of other key personnel, the name of the applicant
institution and other collaborating entities, and the number
and title of this RFA.
Although a letter of intent is not required, it allows NIDDK
Review Staff to estimate the potential review workload and
to avoid possible conflict of interest in selecting
reviewers.
This letter of intent should be sent to:
Dr. Robert D. Hammond
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney
Diseases, NIH
Westwood Building, Room 406
Bethesda, MD 20892
INQUIRIES
NIDDK welcomes inquiries from potential applicants to
clarify any issues or questions regarding this RFA. Such
inquiries should be directed to the following NIDDK Program
Staff:
Dr. Robert E. Silverman
Chief, Diabetes Programs Branch
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney
Diseases, NIH
Westwood Building, Room 626
Bethesda, MD 20892
Telephone: (301) 496-7888
or
Dr. Joan T. Harmon
Executive Director, Diabetes Research Program
Diabetes Program Branch
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney
Diseases, NIH
Westwood Building, Room 622
Bethesda, MD 20892
Telephone: (301) 496-7731
METHOD OF APPLYING
The regular research grant application Form PHS-398 (revised
10/88) must be used. This form is available from the Office
of Grants Inquiries, Division of Research Grants, National
Institutes of Health, Room 449, Westwood Building, 5333
Westbard Avenue, Bethesda, Maryland 20892.
The RFA label available in the 10/88 revision of Application
Form 398 must be affixed to the bottom of the face page.
Failure to use this label could result in delayed processing
of your application such that it may not reach the review
committee in time for review. In addition, the title of the
RFA and the number should be typed on line 2 of the face
page on the
application form.
Submit a signed, typewritten original of the application,
including the Checklist, and four (4) signed, exact
photocopies, in one package to the DRG at the address below.
The photocopies must be clear and on single sides.
Application Receipt Office
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892
At time of submission, send two (2) additional copies of the
application to:
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney
Diseases, NIH
Westwood Building, Room 406
Bethesda, MD 20892
Applications must be received by February 15, 1991. If an
application is received after that date, it will be returned
to the applicant.
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this
RFA that is essentially identical to one that has already been
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.
REFERENCES
1. U.S. Department of Health and Human Services. Report of
the Secretary's Task Force on Black and Minority Health.
Vol. VII, U.S. Government Printing Office, Washington, D.C.,
January 1986.
2. U.S. Department of Health, Education, and Welfare.
Indian Health Trends and Services. U.S. Government Printing
Office. Washington, D.C. 1978. HSA 78-12009.
3. Williams RC, Steinberg AG, Gershowitz H, Bennett PH,
Knowler WC, Pettitt DJ, Butler W, Baird R, Dowda-Rea L,
Burch TA. GM allotypes in American Indians: evidence for
three distinct migrations across the Bering land bridge. Am
J Phys Anthropology 1985, 66:9-19.
REQUEST FOR APPLICATIONS: RFA
RFA: HL-91-02-H
MECHANISMS OF RESTENOSIS AFTER CORONARY ANGIOPLASTY
P.T. 34; K.W. 0715040, 1002004, 0760020
National Heart, Lung, and Blood Institute
Application Receipt Date: March 18, 1991
PURPOSE
The Division of Heart and Vascular Diseases invites grant
applications for up to five years of support for research to
elucidate the fundamental mechanisms responsible for
restenosis after angioplasty, preferably coronary (PTCA).
Applications focusing on peripheral angioplasty will also be
accepted. Applications received in response to this request
will participate in a single competition.
BACKGROUND
PTCA procedures can relieve myocardial ischemia in many
patients with coronary heart disease (CHD) by reducing
luminal obstruction and improving coronary flow. PTCA was
first performed in a patient with coronary artery disease in
1977 and there has been a rapid increase in the number of
angioplasties performed, with over 200,000 in 1988. The
major limitation of PTCA is the high rate of restenosis,
reported to range from 13-48% and peaking 1-3 months after
successful dilatation.
Restenosis is most likely to occur in patients over 60 years
of age, diabetics, smokers, and those with Class IV angina.
The angiographic correlates of restenosis include significant
residual stenosis after dilatation, lesion eccentricity,
lesion length over 10 mm, calcification, proximal lesion
location (particularly in the left anterior descending
coronary artery), and major intimal/medial dissection.
Mechanical factors, such as oversized balloon and high
inflation pressures may also play a role. Other variables
include: a magnitude of stretch with subsequent damage to
deeper layers of vessel wall; and extent of vessel wall
changes resulting from plaque formation and rupture. Thus,
the design of experimental approaches to unravel the
pathophysiology of restenosis presents a considerable
challenge.
PTCA results in unavoidable vessel wall injury. Disruption of
endothelial and vessel wall structure triggers molecular and
cellular responses that lead, in some patients, to restenosis.
Pathological evidence strongly supports the concept of
intimal hyperplasia as the cause of restenosis.
Intimal hyperplasia is a complex process involving
endothelial and vascular smooth muscle cells, platelets,
growth factors, immune responses and the multiple
consequences of disrupting an atherosclerotic plaque.
Platelets are believed to adhere to the arterial wall
immediately after balloon injury and to release growth
factors. Among these growth factors are PDGF and PF4. PDGF
and/or closely related proteins are also produced by injured
smooth muscle and endothelial cells and activated
macrophages. However, there is as yet no direct evidence of
the role of these growth factors in intimal proliferation.
Endothelial cells are also thought to play a major role in
intimal hyperplasia, but the nature of their influence is
unclear. When small vessel wall areas are denuded,
endothelial regrowth is rapid with little intimal
hyperplasia. In large denuded areas, intimal hyperplasia is
greatest in the part of the vessel last to be re-
endothelialized. However, when the denudation is so large
that endothelial cell replication ceases before the injured
area is completely covered, smooth muscle proliferation peaks
soon after injury.
Smooth muscle cell proliferation appears to be an early
response to balloon dilatation of the artery. Cell
replication has been reported to peak within seven days. The
number of cells remains relatively constant after 14 days.
It is postulated that intimal thickening after two weeks
proceeds by cell volume growth and by accumulation of
extracellular matrix and connective tissue, thus giving rise
to the typical fibrocellular lesion. The ultrastructural and
functional properties of the cells in the lesion are typical
of the synthetic phenotype seen in culture, rather than the
contractile phenotype seen in the normal arterial wall.
Little is known about the factors which control the
phenotypic expression of vascular smooth muscle cells in the
setting of a dilated atherosclerotic artery.
Since intimal hyperplasia has been consistently observed in
patients after angioplasty, whether or not restenosis
occurred, it would appear that this narrowing of the dilated
artery is intimately related to the healing process that
follows dilatation. Research directed at elucidation of the
mechanisms of this healing process should afford insights
into the molecular and cellular responses which lead to
restenosis. Although laboratory investigations have led to a
number of important observations, understanding of restenosis
is hampered by the many gaps in knowledge of the biological
determinants of the healing process.
Given the importance of this problem, there have been
clinical assessments of a number of pharmacologic agents
that empirically were thought to have the potential to
prevent restenosis. High-dose steroid therapy, various
calcium channel antagonists, and anticoagulants have shown no
benefit. Although the importance of anti-platelet agents in
preventing acute complications of PTCA has been confirmed,
neither ticlopidine, aspirin-dipyridamole combination,
sulfinpyrazone, nor intravenous dextran have been shown to
prevent restenosis. A small benefit has been reported with
use of more potent anti-platelet agents such as the
prostacyclin analog, ciprostene. Monoclonal antibodies to
platelet receptors are currently being investigated.
Relatively large amounts of omega-3 fatty acids given shortly
before angioplasty and continued for 3 months afterwards have
been shown to reduce the frequency of restenosis in one study
of male veterans. Several promising agents with anti-
proliferative properties are under investigation. These
include low molecular weight/subfragments of heparin, and
ACE inhibitors. Preliminary data indicate that the ACE
inhibitors, cilazopril and captopril, prevent myointimal
proliferation after vascular injury in a non-atherosclerotic
rat carotid artery. Additionally, captopril has been shown
to have anti-atherogenic effects in the Watanabe heritable
hyperlipidemic rabbit aorta. Trapidil (triazolopyrimidine),
a PDGF antagonist, prevented restenosis in an experimental
model. Lovastatin, an HMG-CoA reductase inhibitor, has also
been shown to inhibit smooth muscle proliferation. The
applicability and efficacy of these agents in a clinical
setting remain to be established.
Thus there is a significant need to foster research into the
pathophysiology of restenosis, so that a rational approach
can be developed for modulation of the repair process and
ultimately for prevention of this complication of
angioplasty.
OBJECTIVES AND SCOPE
Applicants are encouraged to submit applications for support
of studies designed to elucidate the fundamental processes
whereby a dilated artery lesion undergoes changes leading to
restenosis. The proposed studies should have clearly stated
hypotheses and be focussed on a well-defined problem.
Interdisciplinary studies are encouraged; however, the format
should be that of the traditional research grant (R01)
application.
PROPOSED RESEARCH
Examples of possible research areas are given below. They
are for illustrative purposes only. Investigators are
strongly urged to consider other relevant approaches:
o Elucidation of the phenotypic changes that occur in
endothelial and vascular smooth cells and fibroblasts in
response to PTCA.
o Evaluation of the changes occurring in the communications
among vascular cells and between vascular cells, platelets
and circulating blood cells during restenosis.
o Elucidation of the pathways whereby immune responses
modulate the activities of vascular cells in restenosis.
o Mechanistic studies of cytokines, mitogens, arachidonic
acid metabolites, and other factors involved in the process of
restenosis.
o Structure, function, and regulation of vascular cell
receptors and transport systems participating in restenosis.
o Elucidation of genetic or other markers which may be
indicators for restenosis.
o Studies of gender differences in the cellular responses to
PTCA.
Investigators should be aware that NIH requires applicants to
give added attention, where feasible and appropriate, to the
inclusion of minorities and women in study populations.
Gender and minority population differences must be noted and
analyzed whenever possible. If minorities and/or women are
not included in a given study, a clear reason for their
exclusion must be provided. Merely including an arbitrary
number of minority group and women participants in a given
study is insufficient to guarantee generalization of results.
EXCLUSIONS
This solicitation deals only with restenosis of coronary
arteries following PTCA. Studies that focus on angiographic
characterization of restenosis, pathologic surveys, long-term
clinical studies, or clinical trials will not be accepted.
Applicants may request equipment; however, funds will not be
provided for major, expensive items or for outfitting a
laboratory.
MECHANISM OF SUPPORT
The support mechanism for this program will be the
traditional, individual research project grant. Although the
financial plans for fiscal year 1991 include $1,000,000 for
the total costs of this program, award of grants pursuant to
this RFA is contingent upon receipt of funds for this
purpose. It is anticipated that up to four grants will be
awarded under this program. The specific amount to be funded
will, however, depend on the merit and scope of the
applications received and on the availability of funds.
Since a variety of approaches would represent valid responses
to this announcement, it is anticipated that there will be a
range of costs among individual grants awarded. It is not
the intent of this announcement to solicit applications for
large studies encompassing a variety of independent projects,
i.e., program projects. If collaborative arrangements
involve sub-contracts with other institutions, the NHLBI
Grants Operations Branch should be consulted regarding
procedures to be followed (tel: 301-496-7536).
Upon initiation of the program, the Division of Heart and
Vascular Diseases will sponsor annual meetings to encourage
an exchange of information among investigators who
participate in this program. In the preparation of the
budget for the grant application, applicants should REQUEST
ADDITIONAL TRAVEL FUNDS for a two-day meeting each year to be
held in Bethesda, Maryland. Applicants should also include a
statement in their applications indicating their willingness
to participate in such meetings.
Applicants, who will plan and execute their own research
programs, are requested to furnish their own estimates of the
time required to achieve the objectives of the proposed
research project. Up to FIVE YEARS of support may be
requested. At the end of the official award period, renewal
applications may be submitted for peer review and competition
for support through the regular grant program of the National
Institutes of Health (NIH). It is anticipated that support
for the present program will begin on September 30, 1991.
Administrative adjustments in project period and/or amount of
support may be required at the time of the award.
All current policies and requirements that govern the
research grant programs of the NIH
will apply to grants awarded in connection with this RFA.
Awards in connection with this announcement will be made to
foreign institutions only for research of very unusual merit,
need, and promise, and in accordance with Public Health
Service policy governing such awards.
REVIEW PROCEDURES AND CRITERIA
Review Method
All applications responding to this RFA will be reviewed for
scientific and technical merit by an initial review group,
which will be convened by the Division of Extramural Affairs,
NHLBI. Upon receipt, applications will be reviewed for their
responsiveness to the objectives of this RFA. If an
application is judged unresponsive at this stage, the
applicant will be contacted and given an opportunity to
withdraw the application or to have it considered for the
regular research grant program of NIH.
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but that has not yet been
reviewed, the applicant will be asked to withdraw either the
pending application or the new one. Simultaneous submission
of identical applications will not be allowed, nor will
essentially identical applications be reviewed by different
review committees. Therefore, an application cannot be
submitted in response to this RFA which is essentially
identical to one that has already been 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 Criteria
The factors to be considered in the evaluation of each
application will be similar to those used in the review of
traditional research project grant applications. The major
factors to be considered in the evaluation of applications
will include:
1 The scientific merit of the proposed projects, including
the originality and feasibility of the approach, and the
adequacy of the experimental design;
2 The competence of the investigators to accomplish the
proposed research goals, their commitment, and the time they
will devote to the program;
3 The adequacy of facilities for performance of the
proposed research including the laboratory facilities, the
proposed instrumentation and, when needed, the data
management systems;
4 The integration of any interdisciplinary components into
a coherent enterprise with adequate plans for interaction and
communication of new information and concepts among the
collaborating investigators;
5 The appropriateness of the budget for the proposed
program.
METHOD OF APPLYING
Letter of Intent
Prospective applicants are asked to submit a one-page letter
of intent that includes identification of any other
participating investigators and institutions, together with a
descriptive title. The National Heart, Lung, and Blood
Institute requests such letters only for the purpose of
providing an indication of the number and scope of
applications to be received and, therefore, usually does not
acknowledge their receipt. A letter of intent is not
binding, and it will not enter into the review of any
application subsequently submitted, nor is it a necessary
requirement for application. This letter of intent, which
should be received no later than January 4, 1991. should be
sent to:
Dr. Charles Turbyfill
Review Branch/Division of Extramural Affairs
National Heart, Lung and Blood Institute
National Institutes of Health
Westwood Building, Room 553
Bethesda, MD 20892
Format for Applications
Submit applications on form PHS 398, (revised 10/88) the
application form for the traditional research project grant.
This form is available in the applicant institution's office
of sponsored research or business office. Use the
conventional format for research project grant applications
and ensure that the points identified in the section on
"Review Procedures and Criteria" in this announcement are
fulfilled. Be sure to observe the new page limitation
requirements.
To identify the application as a response to this RFA, CHECK
"YES" on Item 2 of page 1 of the application and enter the
title "Mechanisms of Restenosis After Coronary Angioplasty"
and the RFA number HL-91-02-H.
IN ADDITION, BE SURE TO ATTACH THE RFA LABEL FROM THE
APPLICATION KIT TO THE BOTTOM OF THE FACE PAGE OF THE
ORIGINAL APPLICATION AND PLACE THIS ON TOP OF THE FOUR
COPIES TO BE MAILED TO THE DIVISION OF RESEARCH GRANTS.
FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING
OF YOUR APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW
COMMITTEE IN TIME FOR REVIEW.
Application Procedure
Send or deliver the completed application and four (4)
signed, exact photocopies of it to the following, making sure
that the original application with the RFA label attached is
on top:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
SEND AN ADDITIONAL TWO (2) COPIES OF THE APPLICATION TO DR.
CHARLES L. TURBYFILL AT THE ADDRESS LISTED UNDER LETTER OF
INTENT. IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME
TIME AS THE ORIGINAL AND FOUR 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 March 18, 1991. An
application not received by this date will be considered
ineligible.
Timetable
Letter of Intent January 4, 1991
Application receipt date March 18, 1991
Review by National Heart, Lung
and Blood Advisory Council September 12-13, 1991
Anticipated Award Date September 1991
Inquiries
Inquiries regarding this announcement may be directed to the
program administrator:
George Sopko, M.D., M.P.H.
Federal Building, Room 3C06
National Heart, Lung and Blood Institute, NIH
Bethesda, MD 20892
Telephone: (301) 496-1081
This program is described in the Catalog of Federal
Domestic Assistance number 93.837, Heart and Vascular
Diseases. Awards will be made under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grant 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.