Subject: RFA HL-9l-06-H Full text
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Tue, 02 Apr 91 13:08 EST

Hi Paul,
  Please post this one to the NIH Listserver as:
     RFAHL-91-06-H.910329
                         Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$FT BEGIN HL-91-06-H ************************************************** P1O1
 
REQUEST FOR APPLICATIONS
 
RFA:  HL-91-06-H
 
KAPOSI'S SARCOMA:  CELL CYCLE STUDIES OF VASCULAR CELLS
 
P.T. 34; K.W. 0715040, 0715035, 1002004
 
National Heart, Lung, and Blood Institute
 
Application Receipt Date:  September 16, 1991
 
PURPOSE
 
The Division of Heart and Vascular Diseases invites grant
applications for up to four years of support for research
into the basic mechanisms involved in the proliferative
patterns of vascular cells in Kaposi's sarcoma (KS).  One
goal of these studies is to acquire knowledge that could
be utilized to develop new approaches to the treatment of
KS.  A second and more general goal is to acquire
knowledge that would have broad application for
understanding the aberrations of vascular cell
proliferation in a variety of diseases in which capillary
cell dysfunction plays a key role.
 
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), 'Kaposi's Sarcoma:
Cell Cycle Studies of Vascular Cells' is related to the priority
area of HIV infection.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0)
or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, D.C. 20402-9325
(telephone 202-783-3238).
 
BACKGROUND
 
Kaposi's sarcoma, which is vasogenic in origin, exhibits
a wide variety of clinical presentations, most notably in
the United States in HIV+ patients.  There is frequent
involvement of mucous membranes, lymph nodes or
gastrointestinal tract, as well as cutaneous sites.
While the disease can be indolent and non-life
threatening, it is often extremely disfiguring.  It can
also be fulminant and, when there is lung involvement, it
can be fatal.  When the eye is involved it can lead to
blindness.
 
Current treatment of KS involves either radiation or
chemotherapy.  The lesions frequently return after
cessation of therapy.  A study of the specific
characteristics of the vascular cells in KS might lead to
new therapies for the disease in AIDS and non-AIDS
patients.
 
Kaposi's sarcoma was originally considered to be a
neoplasm; however, there is much evidence to suggest that
the early lesions, at least, are hyperplastic.  For
example, most solid tumors begin at a primary site and
subsequently metastasize in a predictable fashion, whereas
the lesions of Kaposi's sarcoma do not usually occur at
typical metastatic sites.  Cells from KS grown in vitro
show a heterogeneity that suggests that the tumor has
not developed from a single cell by clonal expansion.
Furthermore, KS occurring in patients who have received
renal transplants will frequently regress when
immunosuppressive therapy is reduced or discontinued.
 
In general, a biopsy of KS shows infiltrating spindle-
shaped cells with a proliferation of small, incompletely
formed blood vessels lined by cells with the
characteristics of endothelium embedded in a network of
reticular and collagen fibers.  The blood vessels may
contain red blood cells and are surrounded by infiltrates
of macrophages, lymphocytes, and plasma cells.
 
A model that encompasses the various stages of KS
evolution states that the initiating factor is the
pronounced lymphoproliferation that occurs following HIV
infection.  Angiogenic lymphokines provoke local
capillary and lymphatic endothelial cell hyperplasia
that then becomes self-perpetuating.  This process is
sustained by growth factors, oncogene activation, and co-
factors such as viral infections, carcinogens, hormones,
and genetic predisposition.  Evidence to support this
model comes from two sources:  (1) the fact that
endothelial cell proliferation can be demonstrated in
apparently normal skin biopsies of HIV+ patients, and (2)
from in vitro studies of cells explanted from biopsies of
KS.
 
Explants of both endothelial cells and spindle cells,
which are believed to be derived from vascular smooth
muscle cells, have been propagated in culture.  The
spindle cells secrete cytokines that are capable of
stimulating endothelial cell and fibroblast growth as
well as having an autocrine effect.
 
Although HIV-1 has not been detected in KS cells, there
is evidence that the tat-protein, which is produced by
HIV-1, may be playing a role.  One laboratory has reported
that tat-protein stimulates in vitro growth of cells by
as much as threefold.  Another group has introduced the
tat-gene into the germ line of transgenic mice.  Fifteen
percent of the males but none of the females expressing
the tat-gene developed lesions resembling KS.  This
finding is of interest because the majority of patients
with KS are male.  The result supports the concept of a
hormonal component among the factors involved in the
pathophysiology of KS.
 
Clearly, KS involves pathologic changes in cell cycle
control of vascular cells.  The availability of cells
from KS provides an opportunity to conduct fundamental
research that may lead, not only to new approaches to
treatment of KS, but also, in a broader sense, to new
understanding of the mechanisms involved in the
development of vascular lesions in other disease states
that are characterized by altered proliferative
patterns.
 
The advent of the powerful tools of molecular biology has
stimulated a great deal of research into the cell cycle,
most studies being conducted on yeast, bacteria,
Drosophila or cancer cells, in addition to embryonic
studies with Xenopus.  There is a definite need to expand
these studies to mammalian cell types, and for this
initiative, specifically to vascular cells.
 
The traditional view of four phases of the cell cycle has
now been expanded into a far more complex picture
involving numerous macromolecular components that are
assembled, activated, and moved.  Moreover, it has now
been shown that the phases are not discrete.  Preparatory
activities for the next phase may overlap with the
ongoing phase.  Application of these recent discoveries
to vascular cells could greatly advance our knowledge of
the fundamental mechanisms that are perturbed in
vascular disease states.
 
In multicellular organisms, a series of signals to
initiate DNA replication is transmitted from outside the
cell to the nucleus.  Growth factors have been
extensively investigated in this regard and the results
have relevance to the problems of cell replication in the
vascular system.  For example, in 3T3 mouse fibroblasts,
platelet derived growth factor (PDGF) is capable of
stimulating initial events that lead to DNA replication;
but epidermal growth factor (EGF), insulin, and possibly
other factors, which are contained in plasma, are necessary
for DNA synthesis.  The G1 phase, during which cells
prepare for DNA synthesis, extends over many hours.  It
has been subdivided into sixteen steps encompassing a
complex series of biochemical events whereby growth
factors combine with their specific receptors that extend
across the plasma membrane of the cell.  Through
phosphorylation and second messengers, signals are
transmitted to regulators in the nucleus where gene
expression is activated.
 
A great deal of research is currently focussed on how
cell proliferation is controlled both from within the
cell and from external growth factors, such as tumor
necrosis factor, interferons, and transforming growth
factor-beta.  Progress has also been made in elucidating
the genetic mechanisms that control cell replication.
For example, the weel-gene has been shown to inhibit the
expression of pp34 by the cdc2-gene.
 
There is an abundance of experimental techniques that
could be applied to the study of vascular cells.
Moreover, this research would provide much new knowledge
applicable to vascular disease in general.  For example,
vascular smooth muscle cell proliferation has been
observed in restenosis following revascularization.
Immunosuppression and cytomegalovirus have been
implicated as co-factors for both KS and the accelerated
atherosclerosis that follows cardiac transplantation.
IL-6 has been implicated as a potent growth factor for
KS.  IL-6 gene expression has been shown to play a role
in angiogenesis.  It has also been shown that
proliferating or IL-1-activated vascular smooth muscle
cells produce large amounts of IL-6.  TNF-alpha is a
contributing factor in the sequelae of Kawasaki disease
where endothelial cell death is not followed by a healing
process.  Other examples of failed vascular growth
include delayed wound healing, nonhealing fractures, and
congenital malformations associated with lack of
capillary growth.
 
KS is more common in men than in women implying a role
for hormonal factors in vascular injury.  Recent research
has revealed a family of steroid and thyroid hormone
receptors that play important roles in the regulation of
gene transcription.  These nuclear receptors may be
involved in the control of capillary growth in vascular
disease states.
 
Thus, a great deal remains to be learned about the
factors that stimulate and inhibit cell cycle activity
in vascular cells.  The availability of human cells from
KS and mouse cells from transgenic animals with KS-like
lesions provide a unique opportunity to study fundamental
properties of these cells.
 
OBJECTIVES AND SCOPE
 
All applications must be focussed on vascular cells and
have relevance to Kaposi's sarcoma.  Studies must be
designed to elicit new information, at the molecular
level, of the control of proliferation in vascular cells.
 
PROPOSED RESEARCH
 
Examples of research projects are given below.  However,
these are provided for illustrative purposes only.
Applicants may consider other projects that
contribute to the goals of this initiative but are not
included in this list.  In all cases, the studies must
include cells derived from KS or an animal model of KS.
 
o  Elucidation of the mechanisms whereby hormones affect
the stimuli that provoke cell replication in vascular
tissue.
 
o  Studies of the growth factors that produce vascular
cellular proliferation.
 
o  Investigations of the mechanisms whereby extracellular
signals governing vascular cell proliferation are
transmitted to the nucleus of vascular cells.
 
o  Elucidation of the mechanisms whereby a virus or viral
fragment can promote a proliferative response in KS
vascular cells.
 
o  Elucidation of the cellular mechanisms that are
inhibited by angiostatic factors.
 
o  Investigations of the mechanisms of action of cell
cycle modulators that have potential as therapies for KS
and other vascular diseases involving pathology related
to cell cycle aberrations.
 
o  Interactions among vascular cells as they relate to
production of factors for stimulation or inhibition of
proliferation.
 
o  Elucidation of the role of the immune system in cell
cycle control in vascular cells.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to
include minorities and women in 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 should be provided.
 
The composition of the proposed study population must be
described in terms of gender and racial/ethnic group.  In
addition, gender and racial/ethnic issues 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 Section 2, A-D of the Research
Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility
of including the broadest possible representation of minority
groups.  However, NIH recognizes that it may not be feasible or
appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority
populations (i.e., Native Americans (including American Indians
or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics).
 
The rationale for studies on single minority population groups
should be provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive 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 and racial/ethnic minorities 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 minorities.
 
If the required information is not contained within the
application, the application will be returned.
 
Peer reviewers will address specifically whether the research
plan in the application conforms to these policies.  If the
representation of women or minorities in a study design 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 application.
 
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.
 
EXCLUSIONS
 
This solicitation is designed to gain insight into
vascular cell cycle dynamics in KS.  Applications
focussed on general concepts of tumorigenesis, on
capillary growth as support for tumor growth, and on the
attachment of non-vascular tumor cells to endothelium
will not be accepted.  The role of viruses or the immune
system in promoting tumor growth in general will also be
outside the scope of this initiative.  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 (RO1).  Although
the financial plans for fiscal year 1992 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 five
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 National Heart, Lung,
and Blood Institute (NHLBI) Grants
Operations Branch must 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 THREE 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 April 1992.  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.
 
ELIGIBILITY
 
All domestic public and private, for-profit and non-profit,
institutions or organizations are eligible to apply in response
to 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
 
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 an opportunity to withdraw the
application or to have it considered for the regular,
investigator-initiated grant program of the 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 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.
 
Applications judged to be responsive will be reviewed for
scientific and technical merit by an initial review
group, which will be convened by the Division of
Extramural Affairs, NHLBI, solely to review these
applications.
 
This initial review will include a preliminary evaluation
to determine scientific merit relative to the other
applications received in response to this RFA (triage).
The NIH will withdraw from further consideration
applications judged to be noncompetitive and promptly
notify the Principal Investigator/program director and
the official signing for the applicant organization.
Those applications judged to be competitive will be
further evaluated for scientific/technical merit by the
usual peer review procedures.
 
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:
 
o The scientific merit of the proposed projects,
including the originality and feasibility of the
approach, and the adequacy of the experimental design;
 
o The competence of the investigators to accomplish the
proposed research goals, their commitment, and the time
they will devote to the program;
 
o The adequacy of facilities for performance of the
proposed research including the laboratory facilities,
the proposed instrumentation and, when needed, the data
management systems;
 
o 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;
 
o The appropriateness of the budget for the proposed
program.
 
METHOD OF APPLYING
 
Letter of Intent
 
Prospective applicants are asked to submit a
letter of intent that includes identification of any
other participating investigators and institutions,
together with a descriptive title.  The NHLBI
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 August
30, 1991, must 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 and the Office of Grants
Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD, telephone
301-496-7441.  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, "Kaposi's Sarcoma:  Cell Cycle Studies
of Vascular Cells" and the RFA number HL-91-06-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 TO 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 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 NINETEEN (19) COPIES OF THE
APPLICATION TO DR. CHARLES L. TURBYFILL AT THE ADDRESS
LISTED UNDER LETTER OF INTENT.  IT IS IMPORTANT TO SEND
THESE NINETEEN 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 September 16, 1991.  An
application not received by this date will be considered
ineligible.
 
Timetable
 
Letter of Intent                   August 1, 1991
 
Application Receipt Date           September 16, 1991
 
Review by National Heart, Lung
and Blood Advisory Council         February 6-7, 1992
 
Anticipated Award Date             March 1992
 
Inquiries
 
Inquiries regarding this announcement may be directed to
the program administrator:
 
Constance Weinstein, Ph.D.
Federal Building, Room 3C06
National Heart, Lung and Blood Institute, NIH
Bethesda, MD  20892
Telephone:  (301) 496-1081
 
For fiscal and administrative matters, contact:
 
Linda Shaw
Grants Operation Branch
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11-D
Bethesda, MD  20892
Telephone:  (301) 496-7536
 
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.
 
$$FT END ***************************************************************