Full Text HL-93-05


NIH GUIDE, Volume 21, Number 42, November 20, 1992

RFA:  HL-93-05-H

P.T. 34

  Cardiovascular Diseases 
  Physiology, Human 

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 1, 1993
Application Receipt Date:  April 27, 1993


The Division of Heart and Vascular Diseases invites grant applications
for up to five years of support for research into the roles of sex
hormones in the physiology and pathophysiology of the coronary
vasculature.  The ultimate goal is to develop insights into therapeutic
approaches for reducing the higher incidence of coronary diseases in
men and post-menopausal women than pre-menopausal women.


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), Effects of Sex Hormones on Coronary Artery
Reactivity, 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 202-783-3238).


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.
Applications from minority individuals and women are encouraged.


This RFA will use the National Institutes of Health (NIH) individual
research grant (R01). Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.
The total project period for applications submitted in response to the
present RFA may not exceed five years.  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.


Approximately $1.5 million in total cost will be provided for the first
year of support for the entire program.  It is anticipated that six new
grants will be awarded under this program.  This level of support is
dependent on the receipt of a sufficient number of applications of high
scientific merit.  Although this program is provided for in the
financial plan of the National Heart, Lung, and Blood Institute
(NHLBI), awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.  Administrative adjustments in
project period and/or amount of support may be required at the time of
the award.  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.



Recent studies reveal that temporary ischemia can occur, not only as a
result of organic obstruction of the coronary artery, but also as a
result of vasoconstriction and vasospasm.  There is evidence that in
many blood vessels, the endothelium as well as the vascular smooth
muscle plays an active role in the control of vascular reactivity.  The
regulation of vascular reactivity, especially in the coronary arteries,
may have a significant effect on vasospasm and the development of
coronary vascular disease.

Gender is one of the major risk factors for the development of coronary
artery disease.  Epidemiological studies show that young men are at
higher risk than young women and that this prominent difference
decreases in post-menopausal women.  Involvement of sex hormones in
vascular reactivity has been suggested frequently but clear evidence
for a mechanism is lacking.  Gender differences in vascular reactivity
have been demonstrated by several research groups which suggest that
the function of the endothelium and vascular smooth muscle are sexually
differentiated and modulated by sex hormones.  In these studies, a
number of vessel segments from female and male animals treated with
estrogen relaxed significantly more in response to both
endothelium-dependent and endothelium-independent vasodilators than did
ring segments from male or female animals treated with testosterone.
In other studies, the tension generated by the vascular smooth muscle
in response to the vasoconstrictors was greater in aortas from male
than female rats.  Moreover, removal of the endothelium and treatment
with testosterone increases the responsiveness of the aorta of female
rats.  These observations suggest that the endothelium of male rats has
a lesser capacity to inhibit contractions of the underlying vascular
smooth muscle, possibly because it releases less endothelium-dependent
relaxation factors under basal conditions.  The expression of gender
differences in vascular responses, however, depends on the vessel
itself.  Although several studies have demonstrated that coronary
vessels from male animals show greater vascular reactivity, the degree
to which coronary smooth muscle and the endothelium are sexually
differentiated and modulated by sex hormones remains to be determined.

It has been suggested that one of the protective effects of estrogens
may be mediated through several systemic and local processes which
include the direct and indirect effects of estrogens on structural
elements of the vessel wall.  Limited but significant data have
identified the presence of androgen, progesterone and estrogen
receptors in the coronary vasculature in experimental animals and
progesterone receptors have been identified in coronary arteries of
men.  However, no attempt has been made to see whether there is a sex
difference in the distribution and density of steroid binding sites.
These results can only be viewed as qualitative information regarding
the existence of hormone-specific target cells.  In fact,
identification of steroid hormone receptors in a potential target
tissue does not necessarily establish physiological function.  Receptor
concentration is influenced by hormonal stimulation, sex, maturation,
aging, and probably many other factors.  These variations should be
taken into consideration while evaluating the effects of sex hormones
on the coronary vasculature.  While recent studies have suggested that
androgen and estrogen may modulate specific functions of aortic smooth
muscle cells and that elevations in circulating concentrations of
endogenous estrogen may influence the function of vascular endothelial
or smooth muscle cells of the coronary artery, a correlation between
steroid hormone receptors and hormonal modulation of cell function in
the coronary vasculature still needs to be determined.  Also, the role
of the coronary reactivity should be evaluated in mature and immature
animals of both sexes in terms of its morphological, pharmacological,
and biophysiochemical characteristics.

Sex hormones interact with the sympathetic nervous system at the
peripheral level.  Testosterone and estrogen have been shown to inhibit
norepinephrine uptake and inactivation in isolated hearts of rats.
Also, gender differences have been described in the distribution of
endogenous catecholamines and in alpha receptor affinity.  These data
suggest that sympathetic control of the vascular reactivity exhibits a
dimorphic pattern due to the action of sex hormones.  The coronary
circulation is predominately regulated by the sympathetic nervous
system.  Physiological stress such as exercise and hypoxia increases
the sympathetic activity of the heart.  Whether or not the coronary
vascular bed responds to these stimuli in a sexually differentiated
manner is still unclear.  The evaluation of the interaction between the
sympathetic mechanism and the sex hormones in this specific vascular
bed will certainly provide important information regarding the
mechanisms underlying coronary vascular disease under normal and
stressful conditions in men and women across all ages.

Objectives and Scope

All applications must be focussed on the role of the sex hormones on
coronary reactivity.  The spectrum of experimental approaches
considered responsive to this RFA includes in vivo and ex vivo studies
of coronary vascular reactivity, co-culture techniques to elucidate
cell to cell interaction, cell receptor density, as well as molecular
pharmacological approaches that will enhance our understanding of how
sex hormones regulate coronary vascular cell function.

Proposed Research

Examples of research projects are given below, however, these are
provided for illustrative purposes only.  Applicants may consider other
projects that may contribute to the goals of this initiative, but are
not included in this list.

o  Identification of the distribution and density of sex hormone
receptors on the coronary vessels under different sex-, age- and
cycle-related conditions.

o  Evaluation of the correlation between sex hormone receptors and
hormonal modulation of cell function.

o  Differentiation between acute and chronic effects of sex hormones on
coronary reactivity.

o  Evaluation of the expression of sexual dimorphism in coronary
vascular reactivity which is controlled by the sympathetic nervous
system under different physiological conditions.

o  Identification of the cellular and molecular mechanisms modulated by
sex hormones.


NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
on study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are excluded
or inadequately represented in clinical research, particularly in
proposed-population based studies, a clear compelling rationale must be

The composition of the proposed study population must be described in
terms of gender.  In addition issues of gender should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the research plan AND
summarized in Section 5, Human Subjects.  Applicants are urged to
assess carefully the feasibility of including adequate numbers of

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and prevention strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women when it
is important to apply the results of the study broadly, and this should
be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will not be accepted for review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women is inadequate to answer the scientific question(s) addressed AND
the justification for the selected study population is inadequate, it
will be considered a scientific weakness or deficiency in the study
design and will be reflected in assigning the priority score to the

All applications for clinical research submitted to NIH are required to
address these policies. NIH funding components will not award grants or
cooperative agreements that do not comply with these policies.


Prospective applicants are asked to submit, by February 1, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to which
the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of applications.
It allows NHLBI 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:

Review Branch
Chief, Centers and Special Projects Section
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 553A
Bethesda, MD  20892


The research grant application for PHS 398 (rev. 9/91) is to be used in
applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Inquiries, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone 301-496-7441.

The RFA label available in the PHS 398 application form must be affixed
to the bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In addition,
to identify the application as a response to this RFA, Check "YES",
enter the title "Effects of Sex Hormones on Coronary Artery
Reactivity", and the RFA number HL-93-05-H on Line 2a of the face page
of the application.

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

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

Send two additional copies of the application to the Chief Centers and
Special Projects Section, at the address listed under LETTER OF INTENT.
It is important to send these two copies at the same time as the
original and three copies are sent to the Division of Research Grants
(DRG).  Otherwise, the NHLBI cannot guarantee that the application will
be reviewed in competition for this RFA.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
may wish to identify the GCRC as a resource for conducting the proposed
research.  If so, a letter of agreement from either the GCRC program
director or principal investigator could be included with the

Applications must be received by April 27, 1993. If an application is
received after that date, it will be returned to the applicant without
review.  The DRG will not accept any application in response to this
announcement 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

Upon initiation of the program, the Division of Heart and Vascular
Diseases will sponsor periodic meetings to encourage exchange of
information among investigators who participate in this program, and to
stimulate collaboration.  Applicants should request additional 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


Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness. Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NHLBI staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an NHLBI peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NHLBI.  The second level of review will be
provided by the National Heart, Lung, Blood Advisory Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  the novelty, originality and feasibility of the approach and the
adequacy of the experimental design

o  the competence of the principal investigator and collaborators to
accomplish the proposed research, and the commitment and time they will
devote to the project

o  the suitability of the facilities to perform the proposed research,
including laboratories, instrumentation and data management systems

o  the appropriateness of the requested budget and duration for the
proposed research

o  adequate plans for interaction and communication of information and
concepts among investigators involved in collaborative studies


Although multidisciplinary approaches are encouraged, it is not the
intent of this announcement to solicit applications for large studies
that would encompass a variety of independent project, i.e., program
projects.  This program will not support clinical trials or large
epidemiological studies.  In general, funds will not be provided for
the purchase and installation of expensive, new equipment.  Awards
under this announcement 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.

The anticipated date of award is December 1, 1993.


Inquiries regarding this announcement may be directed to:

Dr. Isabella Liang
Cardiac Diseases Branch
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
Federal Building, Room 3C06
Bethesda, MD  20892
Telephone:  (301) 496-1081
FAX:  (301) 480-6282

Direct inquiries regarding fiscal and administrative matters to:

Mr. William Darby
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 496-7536
FAX:  (301) 402-1200


This program is described in the Catalog of Federal Domestic Assistance
No. 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 grants policies and Federal regulations,
most specifically 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the Intergovernmental review requirements of Executive
Order 12372, or to Health Systems Agency Review.


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