Full Text HL-96-004

ANGIOGENESIS AND VASCULAR REMODELING IN THE MICROVASCULATURE

NIH GUIDE, Volume 24, Number 40, November 24, 1995

RFA:  HL-96-004

P.T. 34

Keywords: 
  Cardiovascular System 
  Biology, Cellular 
  Biology, Molecular 
  0705048 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 1, 1996
Application Receipt Date:  April 11, 1996

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
THAT MUST BE USED TO PREPARE AN APPLICATION IN RESPONSE TO THIS RFA.

PURPOSE

The purpose of this solicitation is to encourage research on the
molecular, cellular, and physiological mechanisms involved in
determining the structure and arrangement of blood vessels during the
processes of angiogenesis and vascular remodeling.  The Request for
Applications (RFA) focuses on changes that occur at the
microcirculatory level, particularly as they relate to hypertension.

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 RFA,
Angiogenesis and Vascular Remodeling in the Microvasculature, is
related to the priority areas of heart disease and stroke, and
diabetes and chronic disabling conditions.  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
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

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 unusual merit, need, and promise, and in accordance with
Public Health Service policy governing such awards.

Among the disciplines and expertise that may be appropriate for this
research program are cell biology, molecular biology, biochemistry,
immunology, pharmacology, and microvascular physiology.

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 (increments) 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 NHLBI staff.

For this RFA, funds must be requested in $25,000 direct cost modules
and a maximum of nine modules ($225,000 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.

Applicants are expected to furnish their own estimates of time
required to achieve the objectives of the proposed research project.
Up to four years of support may be requested.

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 September, 1996.  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 1996, approximately $1.2
million 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 four new grants will be awarded under
this program.  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

A knowledge of the mechanisms that regulate angiogenesis is important
for understanding normal processes, such as wound healing, that are
characterized by rapid, but controlled, neovascularization.  In
addition, this knowledge will provide important insights for
understanding abnormal angiogenic processes such as those involved in
diabetes mellitus, the origin of new microcirculation in the
atherosclerotic plaque, and the growth of neoplastic tumors.
Furthermore, the potential for manipulating the process of
neovascularization has important implications for the treatment of
peripheral vascular disease, coronary heart disease, and cardiac
hypertrophy, because promoting appropriate vessel growth could
provide a means for restoring nutritive blood flow to ischemic
tissues.

Another area of emerging importance is the vascular adaptation and
complications associated with hypertension.  Hypertension is a
serious public health problem that afflicts more than 50 million
people in the U.S.  It is essential to understand both the genetic
and environmental factors that contribute to its development, and the
phenomenon of vascular remodeling provides an appropriate focus for
such research because it is a measurable incremental pathologic
consequence of hypertension.

In addition to the acute changes in tone, blood vessels are capable
of structural alteration over time.  The types of restructuring
include an increase in vascular mass; vessel wall thickening,
enlargement or dilation; and alteration in capillary density, as seen
in rarefaction, a hallmark of diabetic vasculopathy and essential
hypertension.  The loss of microvascular density seen in chronic
reduced renal mass hypertension is thought to be mediated by
structural degeneration of vascular smooth muscle and endothelial
cells.

Vascular remodeling can be viewed as a physiological protective
response, but it can also contribute to certain circulatory
disorders, such as hypertensive vascular disease, atherosclerosis,
restenosis, and aneurysm formation.  These vascular changes are
likely to enhance vasoconstriction and further reduce blood flow and
reserve, which are major contributing factors to the clinical
complications of hypertension, such as myocardial ischemia and
stroke.

Angiogenesis and vascular remodeling represent two aspects of a
series of events that determines the structure and arrangement of
vascular beds, and understanding the factors that regulate one of
these processes should shed light on regulation of the other.  Both
are complex processes involving cell growth, cell migration, cell
rearrangement, or programmed cell death, as well as production,
degradation, and realignment of the extracellular matrix.  There is
evidence that both restructuring processes are initiated by humoral
factors generated by mechanisms that sense a change of hemodynamic
conditions.  The angiogenic process gives rise to new vessels; the
remodeling process finally leads to structural changes in the vessel
wall or to the loss of microvasculature.

The list of factors known to trigger or influence vascular growth has
lengthened extensively over the past twenty years, and now includes
acidic and basic fibroblast growth factors (aFGF, bFGF), transforming
growth factors TGF-alpha and TGF-beta, epithelial growth factor
(EGF), vascular endothelial growth factor (VEGF), hepatocyte growth
factor, and interleukin-8 (IL-8).  Other molecules are angiogenic in
vivo, but are considered to act indirectly because they are not
mitogenic in vitro.  Heparin, an example of such an indirectly-acting
angiogenic substance, produces its action by releasing bFGF from
storage sites in the extracellular matrix.  Conversely, it is also
recognized that there exists a variety of other molecules,
exemplified by the extracellular matrix protein thrombospondin, that
inhibit endothelial mitogenesis.  In addition, vascular growth and
remodeling are also strongly dependent on the extracellular matrix
(ECM) environment in which they occur.

Currently, most research activities related to vascular remodeling
and hypertrophy in hypertension focus on the endothelial-dependent
growth control of vascular smooth muscle cells, and the effects of
altered blood flow and pressure in larger vessels.  However, changes
in the pre-capillary arterioles are thought to be responsible for the
increased peripheral resistance observed in patients with essential
hypertension.  These vessels are especially important in determining
nutritive blood flow (e.g., coronary reserve) in physiological and
pathophysiological states and are the vessels that determine local
vascular resistance.  How these forces act in the microvasculature is
of considerable interest.

Understanding the action of humoral agents and mechanical forces on
vascular structure will require a knowledge of the specific gene
activity that they provoke.  The techniques being used to probe the
molecular biology of other kinds of endothelial cell function could
be applied to these processes to identify the promoters and cis-
regulatory factors involved in triggering, modulating, and
terminating endothelial and smooth muscle mitogenesis.  Transgenic
animal models could provide a means for examining the effects of
specific genomic changes on angiogenesis and vascular remodeling in
normal vessels.  Additionally, the role of genetic predisposition in
the process and how expression of that predisposition may be
modulated by secondary responses resulting from hypertension require
clarification.

Objectives and Scope

The objective of this program is to elucidate the regulation of
molecular, cellular, and physiological mechanisms involved in
determining the structure and arrangement of the microvasculature
during the processes of angiogenesis and vascular remodeling,
particularly, but not exclusively, in the setting of hypertension.
Research could be directed toward genesis of new capillary
structures, neovascularization, or remodeling of mature arterioles,
venules, or capillary structures, and might include studies of the
role of programmed cell death in rarefaction of the microvasculature.
Whereas most research efforts have focused on the structural changes
in larger arteries, the intention of this solicitation is to direct
attention to the microvasculature.  It is also the intent of this
solicitation to foster studies in cell-culture and small animal
models, rather than in human subjects or primates.

Areas of interest under this program might include studies to
identify the genes, promoters, cis-regulatory elements, and
transcriptional events involved in endothelial or vascular smooth
muscle cell replication.  Also of interest would be exploration of
the genomic basis for terminating the effect of an angiogenic
stimulus.  Transgenic animal models would provide a means for
examining the effects of specific genomic changes on vascular
structure.

It is thought by some that the numerous angiogenic peptides
constitute elements of a cascade, much like that responsible for
blood coagulation.  Others regard changes in vascular structure as
involving an interplay between redundant, reinforcing mitogenic
agents and growth factors, modulated by similarly redundant
inhibitors.  Much current research into the action of these peptides
is highly descriptive, and a need exists for hypothesis-driven
fundamental inquiries into the relationships among the wide array of
such agents.

In addition to humoral regulation, angiogenesis and remodeling are
also strongly dependent on elements of the extracellular matrix
(ECM), and the investigation of how they are affected by substances
produced in the ECM, or by realignment of structural elements of the
ECM, would also be important thrusts for research.  The pericyte, the
vascular wall stromal cell in contact with the abluminal surface of
the capillary endothelium, appears to be another potential
determinant of vascular growth and remodeling.  Clinical observations
indicate that the loss of these cells is associated with abnormal
capillary growth, and experimental studies confirm that pericytes can
inhibit endothelial growth.  Understanding the role that pericytes
play in modulating vascular growth could provide valuable information
about remodeling.

Existing in vivo models of angiogenesis have produced primarily a
descriptive view of this process, and no suitable in vivo models
currently address the vascular remodeling seen in hypertension.
Therefore, the development of in vivo techniques to examine
fundamental mechanisms of regulation involved in angiogenesis or
remodeling at the microvasculature level would be considered an
important research goal, as would the design of cell co-culture
systems to investigate fundamental mechanisms that determine vascular
structure.

Applications addressing vascular remodeling in the setting of
hypertension are of particular interest.  Although understanding of
the processes involved in vascular remodeling is far from complete,
ultimately, the development of novel therapeutic approaches that
target hypertensive remodeling would be highly desirable.

The topics discussed above represent examples of research that would
be responsive to this solicitation, but other types of studies may
also be appropriate.  However, applications that propose only
descriptive studies and do not contain hypothesis-driven research
directed at understanding the mechanisms underlying the regulation of
angiogenesis or vascular remodeling will not be acceptable. Studies
intended to specifically investigate inhibition of angiogenesis would
not be considered responsive to this announcement.

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 February 1, 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 Drive, 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.
These forms are available at most institutional offices of sponsored
research; from the Office of Grants Information, Division of Research
Grants, National Institutes of Health, 6701 Rockledge Drive, Room
3034, MSC 7762, Bethesda, MD 20898-7762, telephone 301-435-0714,
email: girg@drgpo.drg.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.

The following modifications are made to the standard PHS 398
application instructions:

Applications not conforming to these guidelines will be considered
unresponsive to this rfa and will be returned without further review.

o  INITIAL BUDGET PERIOD - Only the names of personnel and level of
effort must be itemized in the Personnel section of the "Detailed
Budget for the Initial Budget Period" (Form Page 4).  In addition,
consultants, equipment, supplies, travel, patient care activities,
alterations and renovations and other needs, should be listed as
appropriate.  Costs are not to be indicated for these individual
items or categories.  If subcontracts are involved, state the name(s)
of collaborating institutions in the "Consortium/Contractual Costs"
section and provide individual budgets as detailed in the
"SUBCONTRACTS" section below.  The "Total Direct Costs" line at the
bottom of the page 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 nine modules ($225,000 direct
costs) per year may be requested.  Any large one-time purchases, such
as large equipment requests, must be accommodated within these
limits.

o  FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets
will remain the same for each year of the period of award (i.e., the
same number of modules requested for each and every budget period).
All necessary costs must be considered when determining the number of
modules to be requested.  However, in the exceptional event that the
number of modules requested must change in any future year,
appropriate justification must be provided.  The "Budget for Entire
Proposed Project Period" (top section of Form Page 5) must include
Total Direct Costs requested for each year and the Total Direct Costs
for the Entire Proposed Project Period.  The Justification section
must be completed based on instructions provided on Form Page 5.

o  SUBCONTRACTS - 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 agreement from each
collaborating institution must be submitted with the application.
Initial and future year budgets for subcontracts must be prepared
using the same guidelines as for the main grant except that total
subcontract costs need not be in $25,000 modules.  Requested amounts
must be based on individual needs of the subcontract and must reflect
both direct and indirect costs.  The subcontract costs are included
in the total budget request, which must conform with the number of
$25,000 modules requested.

o  BIOGRAPHICAL SKETCH - In addition to the standard information
requested on Form Page 6, the applicant has the option of providing
the title and source of any sponsored support relevant to the
proposed research.

o  OTHER SUPPORT - No other support information is required on "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.

o  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.

o  The applicant must 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.

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 given
above in the section on LETTER OF INTENT.

Applications must be received by April 11, 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 and any changes requested in
future years.  The total budget request will be reviewed for
consistency with the proposed methods and specific aims.  The
duration of support will be reviewed to determine if it is
appropriate to ensure successful completion of the recommended 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

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

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

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.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Alfred Small, Ph.D or Michael Lin, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 10193
6701 Rockledge Drive
Bethesda, MD  20892-7956
Telephone:  (301) 435-0565
FAX:  (301) 480-2849
Email: ALFRED_SMALL@NIH.GOV, MICHAEL_LIN@NIH.GOV

Direct inquiries regarding fiscal matters to:

Jane Davis
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 7128
6701 Rockledge Drive
Bethesda, MD  20892-7128
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  JANE_DAVIS@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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