Subject: NIH Guide ll/23/90 RFA HL-91-01-H
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 29 Nov 90 13:34 EST

Hi Paul,
   This is a retransmitted RFA from NIH for the ll/23/90 NIH Guide.
Please post the the NIH Listserver as:
   RFAHL-91-01-H.112390
 Thanks.  Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS
 
RFA:  HL-91-01-H
 
P.T. 34, FC; K.W. 0715115, 0755030, 1002019, 1002004, 1002008,
1002030, 0785025
 
MECHANISMS OF HYPERTENSION IN BLACK MEN AND WOMEN
 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  March 6, 1991
Application Receipt Date:  April 8, 1991
 
PURPOSE
 
The purpose of this Request for Applications (RFA) is to
stimulate studies to elucidate
specific mechanisms underlying the excessive prevalence of
hypertension in black men and women, and to delineate
mechanisms that direct the pathogenesis of hypertension in
blacks, including vascular sequelae such as nephropathy,
cerebral vascular disease, coronary artery disease, and
atherosclerosis in other vascular beds.  This RFA also seeks
to encourage investigations that will examine gender-related
mechanisms associated with the development of hypertension in
blacks.  Due to the multiple dimensions of the disease, a
variety of disciplines and approaches are encouraged, such as
genetic linkage analysis, molecular biology, biochemistry,
physiology, neurobiology, pharmacology, cell and structural
biology, cardiology, and nephrology.
 
BACKGROUND
 
In the United States, hypertension in blacks is a significant
clinical and public health problem.  Not only are blacks more
likely to develop hypertension, but the disease develops
earlier, is often more severe, and is more likely to be fatal
at an earlier age.  Mortality associated with hypertension in
blacks is substantially higher than in whites; there is a
six-fold greater incidence of hypertension-related deaths in
middle-aged blacks compared to middle-aged whites.  Even
among blacks who do not die of hypertension, there is an
increased prevalence of the morbid consequences of this
disease:  stroke is 50 percent higher in blacks compared to whites;
left ventricular hypertrophy or an enlarged heart as a
consequence of hypertension is 30 percent greater in blacks compared
to whites; and kidney failure or end-stage renal disease is 3
times higher in blacks compared to whites.
 
Abnormalities in glucose and insulin metabolism are common in
hypertensive patients, both white and black.  Early
aberrations in insulin-stimulated glucose metabolism or
insulin resistance need to be detected and delineated by
race.  There is a well-recognized association of
hyperinsulinemia with elevated cholesterol, elevated low-
density lipoprotein, and decreased high-density lipoprotein
that potentially contributes to cardiovascular disease
through progressive atherosclerosis.  Little is known
regarding abnormalities in lipid metabolism in blacks,
independent of, or in association with, insulin resistance.
Recently, Williams et al. described a syndrome ("Familial
Dyslipidemic Hypertension"), that is present in 12 percent of
hypertensive whites.  Multigenerational studies on familial
transmission may be able to detect distinctive phenotypes of
black hypertension in which metabolic pathways are linked to
hypertension.
 
Compared with whites, blacks have alterations in renal
function including blunted sodium excretion, blood pressure
sensitivity to sodium load, lower rate of renal blood flow,
higher vascular resistance, and reduced excretion of
kallikrein.  Of particular interest in hypertensive
nephropathy is the observation that some hypertensive blacks
exhibit a reduction in renal function despite seemingly
adequate pharmacologic control of blood pressure.  There is
also evidence of excess end-stage renal disease among
diabetic blacks.  Blood pressure is generally higher in
diabetic blacks than diabetic whites.  It is not known
whether the greater predisposition to hypertension among
blacks contributes to the increased rate of diabetic renal
failure.  Alternatively, a single mechanism may be
determining both the hemodynamic and metabolic expressions of
a vascular disease more common in the black race.
 
Several reports have described racial differences in cellular
cation transport rates.  Sodium-potassium cotransport is
lower in blacks, whereas the hypertension-associated increase
in sodium-lithium countertransport is greater in hypertensive
whites.  Other transport mechanisms that may be related to
biochemical or metabolic variations among blacks include
sodium-hydrogen exchange, sodium-calcium exchange, and
sodium-potassium ATPase.
 
Sympathetic nervous system activity influences blood
pressure, arteriolar tone, glucose/insulin, and lipid
metabolism.  Several studies have shown greater blood
pressure and vasoconstrictor responses to standardized
stimuli in blacks.  The results of these investigations have
provided early evidence of augmented alpha receptor
sensitivity in blacks compared to whites.  These data suggest
differences in peripheral vascular function or structure
resulting in greater vascular resistance in blacks.  Another
possible avenue in the pathogenesis of hypertension and
vascular disease in blacks consists of abnormalities in
sympathetic activity that, in turn, lead to concurrent
derangements of metabolic regulation and blood pressure.
Alternatively, the chronic pressor effect of augmented
adrenergic activity could occur as a sequela to the metabolic
derangement via the mitogenic effects of insulin or related
growth factors on the vasculature.
 
In the young, there are detectable racial differences in some
of these biochemical and physiologic parameters related to
hypertension in black adults.  Black children have lower
rates of aldosterone excretion and lower urinary kallikrein.
Racial differences have been reported in cardiovascular
responses to sympathetic stimuli in childhood.  The Bogalusa
Heart Study has demonstrated racial differences in
cardiovascular development in the young.  Black adolescent
males have greater vascular resistance and there is
echocardiographic evidence of hypertensive changes in cardiac
structure at blood pressure levels in the upper quartiles of
the normal blood pressure distribution.  Thus, another
question is whether or not a metabolic process is directing
early vascular changes, the rise in blood pressure occurring
concomitantly as a consequence of increased peripheral
vascular resistance.
 
It is also important to note that there are indications that
differences in the prevalence and effects of hypertension may
be associated with gender.  Premenopausal women, at any
arterial pressure, have a total peripheral resistance that is
lower than men of the same chronological age.  Furthermore,
clinical and epidemiological studies show essential
hypertension to result in lower mortality in women than in
men.  To complicate these findings, black women show higher
prevalence of hypertension than white women, particularly as
age increases, and black women have a higher prevalence of
obesity - a risk factor for hypertension - than do black men.
Little attention has been paid to fundamental differences
between males and females regarding homeostatic mechanisms
that determine arterial blood pressure, vascular tone, and
resistance.
 
Finally, there is evidence that a significant component of
the hypertensive state is inherited.  Molecular genetic
approaches utilizing family studies (genetic linkage) offer
new approaches for dissecting out the genetic components of
hypertension by providing DNA-based markers.  These genetic
markers can lead to a cascade of important and illuminating
findings on the molecular and pathophysiological bases of
hypertension by providing direct access to the altered genes
in suitably configured American black families.
 
The choice of phenotype is central to the success of genetic
linkage analysis.  The clearest possible results occur with
the use of a discrete, reproducibly measurable trait that can
distinguish affected individuals from non-affected
individuals.  Blood pressure measurements are difficult to
use for phenotype characterization because blood pressure is
unimodally distributed throughout the population, varies in
its day-to-day levels, and is subject to other influences,
such as alterations with age.  One way to minimize this
difficulty is to use "intermediate phenotypes" that are
commonly associated with the hypertensive state and have a
major gene effect.  Some examples that may prove feasible
include cationic transport measurements, hormone levels, and
challenge-response tests.
 
Another way to minimize the problems associated with the use
of blood pressure as a phenotype is to do linkage studies
with sibling-pairs.  This approach is advantageous for a
variety of reasons: there are no assumptions about the mode
of inheritance; it is possible to minimize some variability
effects (for example, the investigator could study siblings
who were all about the same age); there are a lot of
siblings, and they are easier to locate and recruit than
extended families.  Although not as powerful as linkage in
extended families, this is a viable approach that operates
under the assumption that siblings have inherited the same
genetic predisposition.
 
OBJECTIVES AND SCOPE
 
Further research is needed to investigate the mechanisms
underlying the excessive prevalence, morbidity, and mortality
of hypertension in blacks, and to determine the mechanisms
that may underlie disparate findings between black women and
men.  Recent data have identified racial differences in
biochemical, neural, endocrine, and hemodynamic function.
Further investigations are needed to fill the gaps in
understanding the pathways that link these biochemical,
neuroendocrine, or physiologic variations with progressive
hypertensive disease in blacks.
 
A number of examples of suitable research approaches are
given below.  These are meant to be illustrative only, and
are not in any way meant to exclude other MECHANISTICALLY
oriented topics.
 
o  elucidate pathophysiological mechanisms underlying
excessive prevalence, morbidity, and mortality in blacks
 
o  examine gender-related mechanisms associated with the
development of hypertension in blacks
 
o  build on observational data to develop and test
mechanistically oriented hypotheses, such as hypertension in
blacks is primarily:
 
     a.  a disorder of membrane transport systems with major
sequelae cascading from altered handling of calcium by
vascular smooth muscle cells
 
     b.  a renal disorder characterized by an impaired
ability to efficiently excrete a sodium load
 
     c.  a metabolic problem, such as insulin resistance and
hyperinsulinemia, that leads to increased peripheral
vascular resistance
 
     d.  a neurogenic abnormality, leading to altered
adrenergic sensitivity
 
     e.  an endocrine defect that diminishes vasodilation or
augments vasoconstriction
 
o initiate studies to determine specific gene
abnormalities responsible for this polygenic disorder in
black families and use this knowledge to elucidate
molecular, biochemical, and pathophysiological mechanisms.
This approach would include studies to select and identify
appropriate, black family configurations (for example,
sibling-pairs or pedigrees); to phenotypically characterize
their members, to collect, analyze, immortalize, and store
cell lines from these individuals; and to use the DNA to
identify markers and genes for hypertension.
 
MULTIDISCIPLINARY APPROACHES, STUDY DESIGN, AND INCLUSION OF
WOMEN
 
Due to the multifactorial nature of the disease, a
combination of disciplines would be appropriate.  Relevant
disciplines may include, but are not limited to:
biochemistry, physiology, genetics, molecular biology,
cardiology, nephrology, endocrinology, neurology,
pharmacology, cellular and structural biology.  Similarly,
multiple designs and groups (young, middle age, elderly) may
be appropriate.  Studies, which may combine disciplines,
should incorporate into the investigative design controls for
age, body mass, and environmental factors.
 
Investigators should be aware that NIH requires applicants to
give added attention, where feasible and appropriate, to the
inclusion of women in study populations.  Gender differences
must be noted and analyzed whenever possible.  If women are
not included in a given study, a clear reason for their
exclusion must be provided.  Merely including an arbitrary
number of women participants in a given study is insufficient
to guarantee generalization of results.
 
Collaborative work may involve individuals from within an
institution or it may be inter-institutional.
 
EXCLUSIONS
 
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 projects, 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.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the
traditional, individual research grant.  Although
approximately $1.5 million in total costs for this program is
included in the financial plans for fiscal year 1991, award
of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  It is anticipated that 4 to 6 grants
will be awarded under this program.  The specific number to
be funded, however, will depend on the merit and scope of the
applications received and the availability of funds.  Because 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.
 
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 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 in September 1991.
Administrative adjustments in project period and/or amount of
support may be required at the time of the award.
 
If collaborative arrangements involve sub-contracts with
other institutions, the NHLBI Grants Operation Branch should
be consulted regarding procedures to be followed (Tel:  301-
496-7257).
 
All current policies and requirements that govern the
research grant programs of the NIH will apply to grants
awarded under this RFA.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method:  All applications submitted in response to
this RFA will be evaluated for scientific and technical merit
by an initial review group, which will be convened for this
purpose 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, the applicant will be
contacted and given the opportunity to withdraw the
application, or have it considered for the regular NIH grant
program.
 
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 scientific merit of each application will be
similar to those used in the review of traditional research
project grant applications, including:
 
o  the novelty, originality, and feasibility of the approach
and the adequacy of the experimental design, including the
suitability and composition of the study population
 
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 for the work
proposed
 
o  adequate plans for interaction and communication of
information and concepts among investigators involved in
collaborative studies
 
METHOD OF APPLICATION
 
Letter of Intent:  Prospective applicants are asked to submit
a letter of intent that
includes the names of participating institutions and all
investigators, together with a descriptive title.  Such a
letter of intent is not binding and will not enter into
the review of any application subsequently submitted, nor is
it a necessary requirement for application.  Letters of
intent are requested solely for planning purposes.  The NHLBI
Staff will not provide responses to such letters.  Letters of
intent should be received no later than
March 6, 1991, and be addressed to:
 
Dr. Charles L. Turbyfill
Review Branch
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 553
National Institutes of Health
Bethesda, MD 20892
 
Format for Applications:  Submit applications on form PHS-398
(revised 10/88), the application form for the traditional NIH
research project grant.  Copies of this form are available in
the applicant institution's office of sponsored research, or
may be obtained from:
 
Office of Grants Inquiries
Division of Research Grants
Westwood Building, Room 449
National Institutes of Health
Bethesda, MD 20892
 
Use the conventional format for research project grant
applications and ensure that the points identified in the
section above on "Review Procedures and Criteria" are
fulfilled.  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 Hypertension in Black Men and
Women" and enter the RFA number HL-91-01-H in the space
provided.
 
THE RFA LABEL FOUND IN THE FORM PHS-398 APPLICATION KIT MUST
BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL
COMPLETED APPLICATION FORM PHS-398.  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, signed
application and four (4) complete 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 TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES
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, OR THE NHLBI CANNOT GUARANTEE THAT THE
APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA.
 
Applications must be received by April 8, 1991.
 
An application not received by this date will be considered
ineligible.
 
Timetable:
 
Letter of Intent                       March 6, 1991
Application Receipt Date               April 8, 1991
Review by National Heart, Lung,
    and Blood Advisory Council         September 12-13, 1991
Anticipated Award Date                 September 30, 1991
 
Inquiries:  Inquiries regarding this announcement may be
directed to:
 
Dr. Stephen C. Mockrin
Chief
Hypertension and Kidney Diseases Branch
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 4C10
National Institutes of Health
Bethesda, MD 20892
Telephone:  (301) 496-1857
Fax:  (301) 496-9882
 
*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 review by a Health Systems Agency.

ANIMAL RESOURCES PROGRAM