kristoff@NET.BIO.NET (Dave Kristofferson) (10/13/89)
Vol. 18, No. 33, September 22, 1989 - Page 14
FULL TEXT OF RFAs FOR ONLINE ACCESS
RFA: 89-HL-18-B
THE ROLE OF HEMOSTATIC FACTORS AND ENDOTHELIAL CELL
REACTIVITY IN VASO OCCLUSION SICKLE CELL DISEASE
P.T. 34; K.W. 1003002, 1002004, 1002034, 0785070
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE*
Application Receipt Date: March 15, 1990
PURPOSE
The Division of Blood Diseases and Resources (DBDR) of the
National Heart, Lung, and Blood Institute (NHLBI), National
Institutes of Health (NIH), invites research grant
applications for a single competition for the support of
basic and clinical research to clarify the role of cellular,
humoral, and vascular factors of blood coagulation in the
pathophysiology of sickle cell disease and to define new
therapeutic strategies that might help to limit or reverse
the process of vaso occlusion.
DISCIPLINES AND EXPERTISE
Among the disciplines and expertise that may be appropriate
for this research program are hematology, cell biology,
biochemistry, physiology, thrombosis and hemostasis.
ADMINISTRATIVE BACKGROUND
The Sickle Cell Disease Branch (SCDB) of the DBDR
has the responsibility for the
design and administration of a national program to develop
and support clinical and basic research activities to reduce
the morbidity and mortality from sickle cell disease.
SCIENTIFIC BACKGROUND
Sickle cell anemia, an inherited disorder that occurs as a
result of the expression of a mutant beta globin gene, was
the first disease to be described on the molecular level.
This disease is characterized by a
chronic hemolytic anemia and recurrent vaso occlusive
episodes that cause severe pain and widespread organ damage.
The prevalence of sickle cell disease in blacks in the United
States is approximately 1 in 400 black newborns and is a
worldwide problem occurring in the Mediterranean countries,
India, Middle East, Caribbean, and South America. Our
knowledge of sickle cell disease at the molecular, cellular
and clinical levels has advanced significantly over the past
decade. The DNA mutation in sickle cell anemia has been
defined and the ultrastructure of the sickle hemoglobin has
been resolved in great detail. Recent studies on the
clinical course of sickle cell disease have provided new
insight into the morbidity and mortality of this disease
process. Data from these investigations have also yielded
important information necessary for effective management of
symptoms, as well as for the prevention of early
complications associated with this disease. Activation of the
coagulation and fibrinolytic systems appears to play a role
in the complex physiologic interactions of sickle cell
disease. Though these observations have been most frequently
noted during episodes of painful vaso occlusion, some
abnormalities have also been detected in sickle cell subjects
during the steady state. Perhaps, for this reason, it has
been difficult to correlate such findings with the actual
severity of sickle cell disease, and it has been hard to
define the specific role(s) played by disordered hemostasis
in clinical manifestations that, together, are referred to as
sickle cell crises. Because no coherent formulation has
emerged on the role of hemostasis in sickle cell
vaso occlusion, it is essential that basic scientists,
particularly those knowledgeable in the fields of hemostasis
and thrombosis, be encouraged to propose research to
illuminate and relate these complex processes to sickle cell
disease in general and to sickle cell crisis in particular.
Such studies should examine and characterize the involvement
of various humoral amplification systems (e.g. coagulation,
fibrinolysis, complement, and kinin), as well as their
interaction with a number of cellular components (e.g.
platelets, endothelial cells, and erythrocytes). It is hoped
that these studies will define the role of humoral and
cellular factors in sickle cell disease and will open new
avenues for treating or preventing episodes of vaso
occlusion.
There is general agreement that microvascular occlusion is
responsible for painful crises and damage to various end
organs, which together represent the major clinical
manifestations of sickle cell disease. Histologic studies
have shown that blood vessels adjacent to infarcted areas are
occluded by both fibrin and by sickled erythrocytes. Since
this finding does not define whether the activation of
clotting factors took place before or after blood vessel
occlusion by sickled erythrocytes, the pathophysiology of
microvascular occlusion remains poorly defined. Early
investigators thought that impaired blood flow and subsequent
vaso occlusion resulted primarily from the abnormal shape and
reduced deformability of the sickle RBC's. Experimental
evidence that has since been accumulated from a wide variety
of in vitro and in vivo studies (see examples below) clearly
indicates that this theory is far too simplistic, and that
vaso occlusion is a very complicated process involving
cellular, vascular, and humoral factors. A brief synopsis of
the work in this area that has been carried out to date is
presented below.
PLATELETS
Early autopsy reports showing the deposition of fibrin and
platelets in the liver of patients with sickle cell disease
led to studies which searched for a role for platelets or
the coagulation system in the development of painful crises.
In the case of platelets, results were at least suggestive.
During the steady state, sickle cell patients exhibit mild to
moderate thrombocytosis. Platelet counts fall transiently at
the onset of a vaso occlusive event. Over the ensuing 7 to
10 days, platelet counts rebound, leading to markedly
elevated counts in the post crisis period. During the vaso
occlusive crisis, platelet production and turnover have both
been shown to be increased. In addition, circulating
platelet aggregates and megathrombocytes give further
evidence of platelet consumption. It is important to
remember, however, that certain of these abnormalities,
notably thrombocytosis, megathrombocytes, and platelet
aggregates may accompany the postsplenectomy state.
Therefore, at least some of these findings may be related to
the asplenia of adult patients with sickle cell disease.
Unlike the rather consistent findings indicated above,
measurements of platelet release products or in vitro studies
of platelet aggregation, performed both during vaso occlusive
crisis and the steady state, have produced widely discrepant
results. Increased, decreased and even normal aggregation in
response to such agents as ADP, epinephrine and collagen
have been reported. Studies of beta thromboglobulin and
platelet factor 4 release have yielded evidence of increased
platelet turnover in sickle cell crises, while others have
not confirmed this finding. To date, most of these data are
based on studies of relatively small groups of patients with
varying types of sickle hemoglobinopathies (sickle cell
anemia (SS), sickle cell hemoglobin C (SC), S beta
thalassemia, sickle cell trait (AS)). In addition, control
subjects used in most
of these studies were not well matched, and the
concentrations of aggregating agents employed varied from
study to study.
THE COAGULATION CASCADE
Assembly of the procoagulant moieties in the coagulation
cascade require a phospholipid surface, and leads to cleavage
of prothrombin to thrombin, the active serine protease.
While the membrane of the normal erythrocyte does not provide
an appropriate catalytic surface, studies suggest that the
membrane from sickled erythrocytes may do so. Sickling and
unsickling of sickle RBC's destabilizes the lipid bilayer,
thereby altering the lipids exposed on the outer face of the
red cell membrane. Thus, while deoxygenation of normal
RBC's does not influence its membrane phospholipid
composition, deoxygenation and sickling of sickled
erythrocytes leads to the exposure of phosphatidyl
ethanolamine and phosphatidylserine on the outer surface of
the sickled cell. Ordinarily these aminophospholipids are
buried deep in the inner membrane leaflet. Their appearance
is particularly prominent in the regions of the membrane
where long, slender spicules are formed. Fragmentation of
these spicules and shedding from the cell surface results in
the formation of vesicles which have the same lipid
composition as the native erythrocyte. These vesicles are
able to dramatically enhance the rate of thrombin generation
by providing the proper catalytic surface for assembly of the
prothrombinase complex. These spectrin free spicules, which
have phosphatidylserine on their surface, have been
identified in the plasma of patients with sickle cell disease
and perhaps are one of the stimuli responsible for the
hypercoagulable state seen in this disorder. It is perhaps a
consequence of the exposure of these aminophospholipids that
increased plasma levels of fibrinopeptide A, a small peptide
produced by the thrombin cleavage of the alpha chain of
fibrinogen, have been found in the plasma of sickle cell
patients during vaso occlusive crisis.
The role of tissue factor, the initiator of the extrinsic
pathway of coagulation, in sickle cell disease related
coagulation remains largely untouched. It has been known for
more than a century that many tissues contain a potent
procoagulant activity. Early studies of this so called
tissue thromboplastin demonstrated that the biological
activity was composed of both lipid and protein components.
This molecule has now been isolated and cloned. It is
constitutively expressed by some extravascular cells and
inducible in certain cells of the vasculature including
monocytes and endothelial cells. An integral membrane
component, tissue factor is fundamental to hemostasis,
serving to initiate coagulation on cell surfaces by binding
Factor VII. It has also been shown that phosphotidylserine
directly alters tissue factor function, increasing the
catalytic efficiency of the tissue factor factor VII complex.
In 1979, sickled cells were reported to adhere to confluent
monolayers of endothelial cells to a far greater degree than
did normal RBC's. However, because of the static conditions
employed in cell monolayer tissue culture studies, it was
essential that these adherence studies also be performed
under conditions of dynamic flow. To accomplish this,
perfusion devices were designed to allow the study of sickle
cell RBC adherence to vascular endothelial cells under
conditions simulating the wall shear rates present in the
microcirculation. Using this model system, the increased
adherence of sickle cells was confirmed. The adherence was
particularly prominent in those areas where injury to the
endothelial cell produced turbulence and stagnation of blood
flow.
Recent single cell adherence studies, utilizing micropipette
technology, have shown that not only are sickle cells more
adherent to endothelial cells, but also that the degree of
adherence can be markedly influenced by a variety of plasma
factors. Several of these factors seem to be present in
higher concentrations in plasma obtained from patients with
sickle cell disease. It has been suggested that these plasma
factors may be the same adhesive glycoproteins which play a
central role in the adhesion of platelets to damaged
endothelium. However, a similar role for erythrocyte
interaction with such adhesive glycoproteins remains to be
defined. The clinical relevance of sickle cell endothelial
cell adherence is suggested by a variety of studies comparing
samples from sickle cell patients both in and out of
vaso occlusive crisis. Using a "clinical severity index"
score, it was noted that red cells, which were obtained from
individuals with the most severe disease, were far more
adherent to endothelial cells than red cells from patients
with low severity scores. Again, it was noted that plasma
factors could influence the degree of adherence of sickle
RBC's. When suspended in buffer, the number of adherent
sickle RBC's was found to be the same if cells were obtained
from a patient during a vaso occlusive crisis or in the
steady state. If, however, the same sickle RBC's were
suspended in their own plasma, the degree of adherence was
far greater in cells taken from the subject during a vaso
occlusive event. Thus, most investigators have found sickle
cells to be more adherent to endothelial cells than normal
cells. This property of enhanced adherence is promoted by
both turbulence of blood flow and by endothelial cell injury.
The increased adherence appears to be related not only to
cellular differences between normal and sickle RBC's, but
also to a variety of proteins (but not limited to)
fibrinogen, laminin, fibronectin, thrombospondin, and von
Willebrand factor (vWF).
BLOOD RHEOLOGY
The pathogenesis of the abnormal blood rheology that is noted
in patients with sickle cell disease is incompletely
understood. It is clear, however, that disturbances of blood
flow, in general, are influenced by whole blood viscosity.
In sickle cell patients, the abnormalities of cellular
deformability, coupled with increased plasma levels of a
variety of large protein molecules, such as fibrinogen and
fibrinogen-fibrin complexes, cause increased whole blood
viscosity and impaired blood flow. The resulting vicious
cycle causes further vascular occlusion as impairment of
blood flow which, in turn, promotes more and more cell sickling.
These abnormalities of blood flow can also be linked to
sickle cell endothelial cell adherence. Blood of high
viscosity, particularly under conditions of shear, can effect
damage to the endothelium, thereby leading to the deposition
of both platelets and fibrin. (In this regard, it is of note
that periods of vaso occlusion are marked by an increase in
the turnover of both platelets and fibrinogen.) As suggested
previously, endothelial damage and the resulting changes in
blood flow (both turburlence and stasis) can lead to further
increases in erythrocyte endothelial cell adherence.
CONTACT ACTIVATION FACTORS
As early as 1967, abnormalities of factor XI and XII levels
were found in patients with SS disease. Because significant
reductions of Factor XII, prekallikrien, and high molecular
weight kininogen are known to occur in patients with disseminated
intravascular coagulation (DIC),
investigators have recently expanded studies of the role of
coagulation in sickle cell disease by focusing on these
components of the contact activation system. The results
indicated relatively low levels of all three moieties in the
steady state which decreased even further during periods of
vaso occlusive crisis. These results are compatible with
ongoing activation of the intrinsic pathway of blood
coagulation. The activation process is further increased
during periods of vaso occlusion, with consumption of Factor
XII, prekallikrein, and high molecular weight kininogen at
rates unable to be compensated for by hepatic production.
Because kinins mediate vasodilatation, local edema, and pain,
it has been suggested that they may play a role in the
symptomatology of sickle cell crisis. As kinins are
generated by kininogen proteolysis, the increased turnover of
the contact activation factors in sickle cell crisis is
consistent with this hypothesis. While high local levels of
kinins cause arteriolar vasodilatation, they also cause
constriction of small veins. Such mediation of venule
constriction can further increase the interrelated events of
sickling, including stasis and local tissue hypoxia. In at
least one study, however, the degree of decrease in plasma
kininogen did not correlate with severity of symptoms or
physical findings of sickle cell crisis.
In addition to kinin release, contact activation of the
intrinsic pathway of coagulation when Factor XII interacts
with a thrombogenic surface can lead to activation of other
amplification systems including fibrinolysis and complement.
The constant challenge to the integrity of the vascular
endothelium by its interaction with sickled erythrocytes can
lead to loss of endothelial integrity and exposure of
subendothelium. The resulting adhesion of platelets and
Factor XII to collagen in exposed subendothelium promotes
and or sustains the ongoing hypercoagulable state.
FIBRINOLYTIC SYSTEM
The fibrinolytic system in sickle cell anemia patients during
vaso occlusive crisis has been reported to be somewhat
depressed. Therefore, lysis of fibrin formed at sites of
vaso occlusion may be retarded. However, recently published
studies have demonstrated that during vaso occlusive crisis,
fragment D dimer, the product of plasmin degradation of
Factor XIIIa crosslinked fibrin, is generated. In addition,
patients with other complications of sickle cell disease (leg
ulcers, cholecystitis, etc.), elevated levels of fragment
D dimer were found, thus indicating active lysis of fibrin.
These data strongly suggest that Factor XIIa crosslinked
fibrin is constantly being formed and lysed during
vaso occlusive crisis, thus indicating thrombin generation
and fibrinolysis in this setting. Finally, the role of
plasminogen activators and inhibitors has yet to be
investigated in sickle cell crisis.
OBJECTIVES AND SCOPE
This special grant program is for the support of research
designed to further our understanding of the role of
cellular, humoral and vascular factors of blood coagulation
in the pathophysiology of sickle cell crisis and to define
new therapeutic strategies that might help to limit or
reverse the process of vaso occlusion.
EXAMPLES OF RESEARCH PROJECTS
Examples of topics that would be appropriate for this program
are shown below. The list is not to be regarded as complete
or exclusive, and other research areas proposed by
applicants that meet the objectives of this program will be
welcomed by the NHLBI. Representatives areas of research
include:
A The role of abnormal rheology in vaso occlusive crisis.
What role, if any, does stasis in areas of low flow play in
vaso occlusive crises? How much do changes in whole blood
viscosity and the resulting alteration in wall shear rates
contribute to this process? What are the contributions of
adhesive plasma proteins such as vWF and cross-linked fibrin
to impaired blood flow in the microvasculature?
B Erythrocyte endothelial interactions.
Is the reported correlation between erythrocyte endothelial
interaction and severity of vaso occlusion a consistent
observation? What plasma proteins cause the increased
adherence of SS erythrocytes to endothelial cells? Are they
the same or similar to adhesive glycoproteins which promote
platelet adhesion to damaged endothelium? Does the
expression of tissue factor play a role in endothelial cell
erythrocyte interactions? Do sickled erythrocytes or shed
vesicles, similar to platelet microparticles, provide a
proper catalytic surface for the enhanced assembly of the
prothrombinase complex?
C Is platelet activation a component of vaso occlusive
crisis?
What is the basis for increased platelet production and
turnover in sickle cell crisis? Does release of platelet
products occur during the steady state or during crisis?
Does thrombospondin contribute to the adhesion reactions?
Can newer methods (e.g. flow cytometry of platelet activation
antigen) be used to define the role of platelet activation
in sickle cell disease? A careful study with adequate
controls is needed.
What are the roles of prostacyclin synthesis and thromboxane
A in this process? Is there a role for thromboxane
antagonists in this setting?
D What is the status of the endothelium in sickle cell
patients?
Are there specific structural and metabolic alterations of
endothelial cells in sickle cell patients? During
vaso occlusive crisis, is it possible that cytokines and
other factors lead to expression of tissue factor and altered
metabolism of endothelial cells? Since vWF is thought to be
synthesized by the endothelial cells, the higher
concentration and or larger polymers of vWF observed in
sickle cell disease tend to support the hypothesis of an
altered metabolic state in this condition.
What are roles of endothelium derived relaxation or
contractile factors in this process?
Might injury and or other stimuli induce the expression of
tissue factor in endothelial cells thus explaining the
hypercoagulable state in sickle cell disease?
E What role do contact activation factors play in vaso
occlusive crisis?
The levels of Factor XII, prekallikrein and high molecular
weight kininogen are low in SS disease and are further
reduced during crisis. Does this reflect consumption or a
decrease in production?
F Does vWF play any role in sickle cell disease?
What is the etiological basis for elevated levels of vWF in
patients with sickle cell disease? Does any change in vWF
multimer pattern characterize vaso occlusive crisis? Does
this lead to increased adhesion of platelets to the
subendothelium? If so, is there any evidence that such a
change could promote vaso occlusive events?
MECHANISM OF SUPPORT
The support mechanism for this FIVE YEAR program will be the
traditional, individual research project grant (RO1).
Although the financial plans for fiscal year 1990 include
$1.0 million in total costs for this announcement, award of
grants pursuant to this RFA is contingent upon availability
of funds for this purpose.
The specific number will
depend on the merit and scope of the applications
received and 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. While
multidisciplinary approaches are encouraged, it is not the
intent of this announcement to solicit proposals for large
studies encompassing a variety of individual sub projects,
i.e., program projects. If collaborative arrangements through
subcontracts with other institutions are planned, consult the
Chief, Blood Grants Management Section, NHLBI Grants
Operations Branch (301-496-7255) regarding procedures.
Consortium arrangements are allowed but must clearly be
conducive to the goals of the RFA. Applications for grants
proposing clinical studies should include members of minority
groups and women in the study populations. Otherwise, a
clear rationale for their exclusion must be provided in the
application. Awards in response to this announcement will be
made to foreign institutions only for research of very
unusual merit, need, and promise, and in accordance with PHS
policy governing such awards.
Upon initiation of the program, DBDR
will sponsor periodic meetings to
encourage exchange of information among investigators who
participate in this program and other investigators with
related interests. In the preparation of the budget for the
grant application, applicants should request travel funds for
a two-day meeting each year, most likely to be held in
Bethesda, Maryland.
Applicants should also include a statement in the budget
section of their applications indicating their willingness to
participate in such meetings.
THIS IS INTENDED TO BE A FIVE YEAR PROGRAM. However,
applicants 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. It is anticipated that support will begin on
July 1, 1990. The current policies and requirements that
govern the research grant program of the NIH will apply to
grants awarded under this RFA. Administrative adjustments in
project duration and amount may be required at the time of
award. During the final year of support, renewal
applications may be submitted for further competitive review
through the regular grant program of the NIH.
REVIEW PROCEDURES AND CRITERIA
Review Method: Applications submitted in response to this
RFA will be reviewed by the NHLBI to determine if they
satisfy the criteria of the RFA. If an application is judged
unresponsive at this stage, the applicant will be contacted
and given an opportunity to withdraw the application or to
have it considered for the regular research grant program of
the NIH. Every effort will be made to include
unresponsive applications in the same review cycle, but this
may not be possible. All responsive applications will be
reviewed for scientific and technical merit by an initial
review group, which will be convened by the Division of
Extramural Affairs of the NHBLI, solely to review these
applications.
If an application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, the applicant will be asked
to withdraw one of them. Simultaneous submission of
identical applications will not be allowed.
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 the novelty,
originality, and feasibility of the approach; the training,
experience, and research competence of the investigator(s);
the adequacy of the experimental design; the suitability of
the facilities; and the appropriateness of the requested
budget to the work proposed.
METHOD OF APPLYING
Letter of Intent: The Institute requests that prospective
applicants submit a one-page letter of intent that includes a
descriptive title and identification
of any other participating institutions. Such letters are
requested only for the purpose of providing an indication of
the number and scope of applications to be received,
therefore their receipt is usually not acknowledged. 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.
This letter of intent should be sent by January
l5, 1990, to:
Dr. Charles L. Turbyfill
Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
Westwood Building, Room 553
Bethesda, Maryland 20892
Format for Applications: Applications should be submitted on
the traditional research project grant application form, PHS
398 (revised l0/88). This form is available in an applicant
institution's office of sponsored research or business office
or may be obtained from the following:
Office of Grants Inquiries
Division of Research Grants
NIH, Bethesda, Maryland 20892
Telephone: (30l) 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" 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 and RFA Number:
"HEMOSTASIS AND ENDOTHELIAL REACTIVITY IN SICKLE CELL
DISEASE," RFA 89-HL-18-B.
THE RFA LABEL (AVAILABLE IN THE l0/88 REVISION OF APPLICATION
FORM 398) MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF
THE ORIGINAL COPY OF THE APPLICATION. FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION.
APPLICATION PROCEDURE
Send or deliver the completed application and four (4)
signed, exact photocopies of it to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892**
Send an additional two (2) copies of the application to
Dr. Charles L. Turbyfill at the address listed under Letter
of Intent.
IT IS IMPORTANT TO SEND THESE 2 COPIES AT THE SAME TIME AS
THE ORIGINAL AND 4 COPIES ARE SENT TO THE DIVISION OF
RESEARCH GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT
THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA.
Applications must be received by March 15, 1990. An
application not received by this date will be considered
ineligible.
TIMETABLE
Letter of Intent January l5, 1990
Application Receipt Date March 15, 1990
Review by the National Heart, Lung,
and Blood Advisory Council September 6-7, 1990
Anticipated Award Date September 30, 1990
INQUIRIES
Inquiries regarding this announcement, including
clarification of the scope, organization, requirement, and
features of the announcement, as well as assistance on the
specific details of the application procedure, may be
directed to:
Dr. Charles A. Wells
National Heart, Lung, and Blood Institute
National Institutes of Health
Federal Building, Room 508
Bethesda, Maryland 20892
Telephone: (301) 496-6931
Consultation as early as possible in the planning stage is
strongly encouraged.
The programs of the Division of Blood Diseases and Resources
are described in the Catalog of Federal Domestic Assistance,
No. 13.839, Blood Diseases and Resources. Awards will be
made under authority of the Public Health Service Act,
Section 301 (42 USC 241) and administered under PHS grant
policies and Federal Regulations 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.
------------------------------------------------------------------------
NATIONAL INSTITUTE OF
ALLERGY AND INFECTIOUS DISEASES (NIAID) AIDS INSTITUTIONAL
TRAINING GRANTS (T32)
NIH-NIAID-89-AI-20
P.T. 44; K.W. 0715008, 0720005, 0765033, 1002008, 1002045, 0755025, 0710030
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Letter of Intent Receipt Date: November 17, 1989
Application Receipt Date: January 10, 1990
This Request for
Applications (RFA) is for the development
of institutional training grants to fund long-term
training in AIDS research.
I. BACKGROUND
Studies of pathogenic mechanisms, and development of
vaccines and therapeutics require close collaboration
between clinicians and epidemiologists working with
HIV-infected patients and basic research scientists in
biochemistry, chemistry, immunology, molecular
biology, pharmacology, virology, and biostatistics.
The collaboration between clinicians and basic
research scientists requires individuals appropriately
trained in multiple disciplines who have developed an
understanding of the requirements and limitations of
each discipline. Recognizing this need, the NIAID
Divison of AIDS is establishing a multi-disciplinary
postdoctoral training program in AIDS research.
II. OBJECTIVES AND SCOPE
AIDS Institutional Training Grants will be awarded by
the Basic Research and Development Program (BRDP),
Division of AIDS, NIAID, and administered by the
Pathogenesis Branch of BRDP. These grants will fund
programs for long-term training in AIDS research.
Grants will be made to successfully competing
institutions for a period of up to five years. The
Division of AIDS anticipates that $875,000 will be
available to support the AIDS Institutional Training
Grant Program in FY90. The review criteria are those
for National Research Service Award (NRSA) T32
Research Training Grants with some modifications. The
initial expedited review of these applications will be
performed by the relevant subcommittee of the AIDS
Research Review Committee. Secondary review will be
conducted by the NIAID Advisory Allergy and Infectious
Diseases Council in May 1990.
The BRDP encourages
applications focusing on the biological mechanisms by
which immunodeficiency viruses cause disease and on
mechanisms of prevention and treatment. Strongly
encouraged are novel studies addressing the
pathogenesis of HIV infection, potential avenues for
enhanced and/or selective immune protection, and
potential strategies for effective drug development.
Some of the research areas which may be addressed are:
mechanisms of T4 cell depletion, mechanisms of
functional alteration of T4 and T8 cells, factors
regulating latency or suppression of viral production,
possible pathogenic roles of defective viruses,
mechanisms of variant virus production and the
significance of genetic variation in the escape from
protective host defenses, importance of viral
integration in T4 cells and macrophages, mechanism of
cell-cell virus transfer, mechanisms of virus mediated
or initiated autoimmune self-destruction, cellular
factors necessary for latency or lytic infection,
development of humoral and cellular immunity,
stimulation of lymphocyte subsets with viral antigens
or peptides, and biochemistry and pharmacology of
novel therapeutic agents.
A. Eligibility
AIDS Institutional Training Grants are available on a
competitive basis to domestic institutions under the
terms of the National Research Service Act of 1974.
Trainees must be United States citizens or nationals,
or must have been officially admitted to the United
States as permanent residents.
B. Minority Recruitment
The policy of NIAID and National Institutes of Health
(NIH) is to promote broad and
systematic efforts to recruit individuals from
minority groups currently underrepresented in
biomedical research. Applicants must provide a
description of special plans or efforts to recruit
minorities to the Institutional AIDS Training Program.
Applications without such specific plans will be
judged not responsive and returned without review.
The following list of potential elements of a minority
recruitment plan is intended as a guide. Applicants
should provide detailed descriptions and explore other
options.
o Advertisements actively recruiting minorities to
the program.
o Posters and flyers actively recruiting
minorities.
o Visits by the program director to minority
institutions.
o Cooperative programs with minority institutions.
o Procedures to identify minority applicants.
o Mailings to minority groups from various lists.
o Invitations to prospective minority applicants
using institutional funds.
C. Program Content
An applicant institution should propose a program in
accordance with the following guidelines:
o Training is limited to postdoctoral fellows
(Ph.D. or M.D.) for a maximum of three years per
trainee.
o Training programs are encouraged in which the
training faculty include both basic research
scientists and clinicians working with AIDS
patients.
o Research projects jointly sponsored by two or
more laboratories with different disciplines are
strongly encouraged.
o If research includes patient care activities,
this activity may not require more than 20
percent of the trainee's time.
o Training should be interpreted as the
acquisition of new skills outside the area of
the trainee's doctoral experience.
o Training grant funds are to be used exclusively
for trainee stipends, medical insurance, and
travel to scientific meetings. It is the
intention that trainees be located in research
laboratories with adequate active research
support. Therefore, no support for faculty
salary, tuition, administration, equipment,
supplies or indirect costs should be requested.
o The budget should include a request for travel
funds for both an annual meeting of AIDS
postdoctoral fellows sponsored by the Division
of AIDS in Bethesda and an AIDS-related
scientific meeting.
o To provide funding for the maximum number of
applications possible, it is the intention that
AIDS Institutional Training Grants be limited to
$175,000/year per application. This level of
support should be sufficient for four or five
fellows.
III. MECHANISM OF SUPPORT
A. Awards will be made as institutional training grants
(T32). Responsibility for the planning, direction,
and execution of the proposed training will be that of
the applicant.
B. NIAID has set aside $875,000 in total costs for the
initial year's funding, and awards in total costs of
$175,000/year per application will be made for up to
five years. It is anticipated that 5 awards will be
made.
C. Only domestic institutions are eligible to apply for
this funding.
D. All policies and requirements that govern the grant
program of the U.S. Public Health Service (PHS), and
the NIH apply.
E. Although this program is provided for in the financial
plans of the NIAID, awards pursuant to this RFA are
also contingent on the continuing availability of
funds for this purpose.
F. The Division of AIDS may consider program goals in
addition to priority scores in funding decisions.
IV. LETTER OF INTENT
Prospective applicants are asked to submit by November
17, 1989, a letter of intent that includes a
descriptive title and a description (not to exceed one
page) of the proposed research. The letter of intent
is requested in order to provide an indication of the
number and scope of applications to be reviewed and
provides a means of early contact between prospective
applicants and NIAID staff and making early
preparations for review. The letter of intent does
not commit the sender to submit an application, nor is
it a requirement for submission of an application.
The letter of intent should be sent to:
Dr. Gregory Milman
Chief, Pathogenesis Branch
Division of AIDS, NIAID, NIH
6003 Executive Boulevard, Room 242P
Rockville, MD 20892
Telephone (301) 496-8378
V. REVIEW METHOD AND PEER REVIEW CRITERIA
A. Consequence of Lack of Responsiveness to RFA
Applications that are incomplete for review or not
responsive to this RFA will be identified by NIH staff
upon receipt and returned to the applicants without
further consideration.
B. Consequences of Late Submission
In light of accelerated solicitation to award
processing requirements mandated by Section 2302 of
the Title II (AIDS amendment of 1988), the receipt
date announced in this RFA must be strictly adhered
to. No exceptions will be made. All applications
received past the receipt date will be returned to the
applicant.
C. Peer Review of Responsive Applications
Applications that are complete and responsive may be
subjected to a triage by a peer review group to
determine their scientific merit relative to other
applications received in response to this RFA. The
NIH will withdraw from competition those applications
judged to be noncompetitive and notify the applicant
and institutional business official.
Those applications judged to be competitive will be
further reviewed for scientific and technical merit by
a AIDS Research Review Committee, NIAID, NIH. The
second level of review will be provided by the
National Advisory Allergy and Infectious Disease
Council.
Review Criteria
Applicants should address the following criteria which
will be employed by the AIDS Research Review Committee
in evaluating applications. The criteria are the same
as those used for evaluating other NRSA applications
but have been expanded to take into account the
special emphases in the new program.
o Scientific merit of the long-term training
program including program objectives and program
design.
o The proposed or ongoing research programs and
the role of the trainees in these programs.
o Multi-disciplinary nature of proposed program.
o Scientific environment and active resources of
the applicant institution including current AIDS
research support.
o Cohesiveness of program including mechanisms for
promoting interdisciplinary exchange of
information such as seminar series, journal
clubs, laboratory rotations, and research
presentations.
o The applicant's ability to attract high-caliber
trainees.
o Description of the steps to be taken for
recruitment of individuals from minority groups.
o Qualifications of training faculty, the
relevance of their current research activities
to AIDS research, and their previous research
training experience.
o Extent of commitment of the institution to the
proposed training program.
VI. METHOD OF APPLYING
A. Receipt Date
The deadline for receipt of applications is January
10, 1990. Applications received after this date will
be considered as not responsive to this RFA and will
be returned without review.
B. General
1. The research grant application form PHS-398 (revised
10/88) must be used in applying. The application kit
contains special instructions for preparing NRSA
institutional fellowship award applications. The PHS
398 forms are available at most institutional business
offices or from the Division of Research Grants,
National Institutes of Health, Room 449, Westwood
Building, Bethesda, MD 20892.
o Submit a signed, typewritten original of the
application, including the Checklist and four (4)
signed, exact, single-sided photocopies, in one
package to:
DRG AIDS Coordinator
Division of Research Grants
National Institutes of Health
Westwood Building - Room 240
5333 Westbard Avenue
Bethesda, MD 20892
o Submit, in addition, 19 exact photocopies of
the application and six (6) copies of appendices
(appendices are optional) to:
Dr. John Meyer, Executive Secretary
Basic Science Subcommittee II
AIDS Research and Review Committee
Program and Project Review Branch
Division of Extramural Activities
NIAID, NIH
Westwood Building, Room 3A-11
Bethesda, MD 20892
Telephone (301) 496-8426
2. TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH
THIS RFA:
a. The application form should have "NIAID AIDS
Institutional Training Grants" (RFA 89-AI-20)
typed on line 2 of the face page of the
application form.
b. The RFA label provided with the instructions
must be affixed to the bottom of the face page.
Failure to use this label could result in
delayed processing of your application so that
it may not reach the review committee in time
for review.
VI. INQUIRIES
o Inquiries of Programmatic nature should be addressed
to Dr. Gregory Milman.
o Inquiries pertaining to review of applications should
be addressed to Dr. John Meyer.
o Inquiries regarding fiscal matters should be addressed
to Ms. Mary Kirker:
Ms. Mary Kirker
Grants Management Branch
Division of Extramural Affairs
NIAID, NIH
Westwood Building, Room 710
Bethesda, MD 20892
Telephone (301) 496-7075
This program is described in the Catalog of Federal Domestic
Assistance, 13.856 - Microbiology and Infectious Diseases
Research and 13.855 - Immunology, Allergic and Immunologic
Diseases Research. Grants are awarded 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 at 42 CFR Part 52 and 45 CFR
Part 74. This program is not subject to review by a Health
Systems Agency.
------------------------------------------------------------------------
RFA 89-HD-09
SPECIALIZED RESEARCH CENTER PROGRAMS IN REPRODUCTION (P50s)
OR CENTER CORE GRANTS TO SUPPORT REPRODUCTION RESEARCH
(P30s)
P.T. 04; K.T. 0413002, 0710110, 0710115, 0710030, 0785105, 0760025
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
Application Receipt Date: June 11, 1990
The National Institute of Child Health and Human Development
(NICHD) provides funding for a limited number of research
centers in the area of population research. These centers
are broadly based investigative endeavors encompassing
research of a biomedical nature. They are supported through
either Center Core Grants (P30) or Specialized Research
Center Grants (P50).
These centers are considered a national resource. They form
a national network that fosters communication, innovation,
and high quality research. Population Research Centers
provide a stimulating, multidisciplinary environment that
attracts and nurtures both established and promising young
investigators. Each Center participating in the Center
Network works closely with NICHD staff in carrying out its
objectives in a manner consistent with the goals and
missions of the NICHD.
BACKGROUND
The Reproductive Sciences Branch (RSB) of the Center for
Population Research (CPR) of the National Institute of Child
Health and Human Development (NICHD) supports basic and
clinical research on human reproduction which relies on a
variety of approaches in the biomedical sciences. Among the
grant mechanisms used to provide research support, the RSB
uses:
1) Specialized Research Center Grants (P50s), which support
integrated groups of research projects and supporting core
service facilities. The research activities included in
such project grants must comprise, by definition, a
multidisciplinary approach to biomedical problems in
reproduction. These research programs may have more than
one theme, focus, or emphasis when all of them are
responsive to one or more specific research areas of
reproduction promulgated by the CPR.
2) Center Core Grants (P30s), which support Center Core
facilities designed to enhance the existing federally
supported research projects within the purview of the RSB,
CPR, NICHD. Such center awards require a critical mass of
individual awards where coordinated technical support would
be cost-effective to the NIH. Although Core Grants provide
no funds for the direct support of research projects other
than for new program development, by making cost-effective
resources and facilities available they enhance the
productivity of existing projects either integrated into a
specialized research area or organized within a central
theme of research.
At present, the RSB supports a fixed number of centers with
a commitment of five years of support that is
competitively renewable for additional five-year periods.
Two P50 centers and two P30 centers will seek
renewal in FY 1991. In addition, one new center grant (P50
or P30) will be awarded in FY 1991. This RFA, therefore,
represents a competition for a total of five grant awards.
RESEARCH GOALS AND SCOPE
The ultimate goals of biomedical research in the
reproductive sciences are to develop new knowledge leading
to clinical applications that will enable men and women to
control their fertility with methods that are safe,
effective, inexpensive, reversible, and acceptable to
various population groups, and to overcome problems of
infertility and reproductive disorders. The Reproductive
Sciences centers designated as "Specialized Population
Research Centers" (P50s) and as "Population Research
Centers" (P30s) are awarded funds for the support of
comprehensive population research programs of high quality
that focus on topics deemed to be of high priority and
significance because of their critically important
relationship to the mission of the CPR. Such topics
currently include reproductive neuroendocrinology,
reproductive endocrinology, reproductive biology,
reproductive genetics, and biomedical studies related to
potential fertility regulating methods or human infertility.
In order to receive funding, a grant for a specialized
population research center (P50) must have three (3) or more
related, integrated, and high quality research projects that
provide a multidisciplinary, yet thematic, approach to the
problems to be investigated. These research projects may be
accompanied by an appropriate number and type of core
facilities providing cost-effective technical support.
A grant for a population research Center Core facility (P30)
must be predicated on the existence of a substantial number
of eligible, funded research grants which will be active on
April 1, 1991. The funded grant group must hold relevant
NIH or other federally funded grants. These grants must
support active users of the core facilities and services
proposed in the center grant application and represent
scientific research relevant to the mission of the CPR.
Because population research center grants are complex
entities, interested applicants should contact
the RSB staff for a consultation regarding the center
programs.
This RFA is specifically designed to stimulate the
reproduction research community to organize or to maintain
population research centers of outstanding standards which,
serving as national research resources, form a network that
fosters communication, innovation, and high quality
research. Applications are encouraged for, but not limited
to, the biomedical topics listed below:
1. Neuroendocrinology of reproduction: Clarification of
the regulatory mechanisms of the hypothalamo-pituitary-
gonadal axis
2. Regulatory mechanism(s) of gonadal function
3. Regulatory mechanism(s) of gametogenesis
4. Mechanism(s) of follicular selection, atresia and
ovulation
5. Mechanism of action of reproductive hormones
6. Structure and function of reproductive hormones
7. Studies on fertilization, preimplantation development of
embryos, or blastocyst implantation
8. Mechanisms regulating genital tract functions
9. Immunological mechanisms regulating fertility
MECHANISM OF SUPPORT
The support mechanisms of these programs are the P50
Specialized Population Research Center Grants and the P30
Population Research Center Core Grants mechanisms. Although
this solicitation is included in the plans for FY 1991,
support for these center grants is contingent upon the
receipt of funds for these purposes. The number of grants
to be awarded is also contingent upon a sufficient number of applications
receiving a high enough level of merit to be
considered for an award. It is expected that up to five (5)
awards will be made as a result of this announcement. The
applications should be
prepared in a manner consistent with the guidelines
presented in the publications entitled either P50
SPECIALIZED RESEARCH CENTER GRANT GUIDELINES or P30 CENTER
CORE GRANT GUIDELINES which are available from the NICHD
offices listed below. The current policies and requirements
that govern the research grant programs of NIH will prevail
(Code of Federal Regulations, Title 42, Part 52 and Title
45, Part 75).
Applications for grants involving clinical studies should
include members of minority groups and women in the study
populations. Otherwise, a clear rationale for their exclusion
must be provided in the application.
REVIEW PROCEDURES AND CRITERIA
An administrative review of the application will be
performed by the Review, Program, and Grants Management
staff for conformance to NIH policy and NICHD guidelines, as
well as for relevance to the program purview of the RSB.
Applications that fail to comply with NIH policy and/or NICHD
guidelines will be formally returned to the applicant.
Applications may be subjected to a triage by a peer review
group to determine their potential competitiveness relative
to other applications submitted. The Institute will
withdraw from competition those applications judged by the
triage procedure to be noncompetitive and notify the
applicant and institutional business official. Those
applications judged to be competitive will be further
evaluated by peer review for scientific/technical merit.
The Executive Secretary of the Population Research Committee
(PRC) may forward the application to selected members of the
PRC for their evaluation to determine if a site visit is
needed. A site visit is not a prerequisite, however, for
consideration of an application by the PRC, NICHD. If a
site visit is required, the Executive Secretary will
communicate with the applicant for the visit arrangements as
described in the guidelines. All competitive applications
received in response to this RFA will be reviewed on a
nationwide competitive basis. The initial review for
scientific merit will be carried out by the PRC. The
second-level review will be made by the National Advisory
Child Health and Human Development Council.
The earliest possible funding date
is April 1, 1991. Review procedures and criteria are
detailed in the P50 SPECIALIZED RESEARCH CENTER GRANT
GUIDELINES and P30 CENTER CORE GRANT GUIDELINES (available
from the NICHD offices listed below).
METHOD OF APPLYING
Interested applicants should contact the RSB staff for an
advisory consultation regarding reproductive sciences center
grants (P50s and P30s). If an applicant intends to apply,
it is strongly recommended, but not mandatory, that potential
applicants send a letter of intent to the RSB staff at the address
listed below by January 1, 1990.
This letter should outline the organizational structure of
the proposed center, list the titles of the relevant research projects
to be associated with it, and the names of the relevant
principal investigators. The letter of intent should be
received by the RSB no later than January 1, 1990, but
applicants are encouraged to send it as soon as they decide
to apply for the grant so that the RSB staff can be of
maximum assistance in the application process.
The standard grant application forms (PHS-398 rev. 10/88)
are used to prepare these applications. The RFA number
and the type of
center grant request (P50 or P30) should be indicated on the
face page of the application in item #2. The RFA label
available in the 10/88 version of PHS Form 398 must be
affixed to the bottom of the face page. Failure to use this
label could result in delayed processing of the application
such that it may not reach the review committee in time for
review. The PHS-398 form is available from most business
offices or grant/contract offices at most institutions and
can also be obtained from NIH by calling 301/496-7441.
It is especially important that applicants note the
supplemental NICHD guidelines, which require certain
tabulations in addition to the usual instructions.
Applications must be submitted by June 11, 1990. Send or
deliver the original, completed, signed application and four
(4) complete copies to:
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892**
In addition to those applications mailed to the Division of
Research Grants, two (2) copies of the application should be
sent under separate cover directly to:
Laurance Johnston, Ph.D.
Scientific Review Program
National Institute of Child Health and Human Development
National Institutes of Health
6130 Executive Boulevard, Suite EPN-520
Bethesda, Maryland 20892
Late applications will not be accepted and will be returned
to the applicants.
For further information contact:
Koji Yoshinaga, Ph.D.
Reproductive Sciences Branch
Center for Population Research
National Institute of Child Health and Human Development
National Institutes of Health
Executive Plaza North, Room 603
Bethesda, Maryland 20892
Telephone: 301/496-6515
This program is described in the Catalog of Federal Domestic
Assistance No. 13.864, Population Research. Awards will be
made under the authority of the Public Health Service Act
301 (42 USC 241) and 441 (USC 289d) and administered under
PHS Grant Policies and Federal Regulations 42 CFR Part 52
and 45 CFR Part 74. This program is not subject to A-95 or
Health Systems Agency review.
------------------------------------------------------------------------
SUPPLEMENTAL INSTRUCTIONS - SMALL GRANTS
PROGRAM FOR LABORATORY RESEARCH RELATED TO THE CLINICAL
EVALUATION OF AIDS THERAPIES
P.T. 34; K.W. 0715008, 0785035, 0745000, 0715125, 0755015, 0755010
National Institute of Allergy and Infectious Diseases
Applications are to be submitted on the standard PHS
research grant application form (PHS-398, Rev. 10/88),
following the instructions supplied with those forms EXCEPT
for the following (see pages 12-23, Instructions Sheet for
PHS-398):
Section 1.
1. Face page of application:
Item 2: Mark "Yes" and enter: Small Grants
Program for Laboratory Research Related to
the Clinical Evaluation of AIDS Therapies,
NIAID.
Item 6: Only one or two years of support is
provided.
Item 10: Not applicable; mark N/A.
2. Application page 4 and 5: Detailed budget for the first
and second year (optional) must be limited to the following
categories: personnel, supplies, and small equipment
items. The total award request for a 1-2 year period
may not exceed a maximum of $45,000
direct costs.
3. Biographic data: Not to exceed one page for principal
investigator. List most important positions and
relevant publications.
4. Other Support: Applicant should identify other AIDS
NIAID, Division of AIDS funding, e.g., Centers for AIDS
Research (CFAR), etc.
Section 2.
1. Introduction: Not applicable.
2. Research Plan
A. Specific Aims: Not to exceed one-half page.
B. Background and Significance: Not to exceed one
page.
C. Progress Report/Preliminary Studies: A progress
report is not applicable. If data from
preliminary studies are available, the report
should not exceed one-half page. Since this
award mechanism intends to fund pilot projects,
preliminary data are not required.
D. Experimental Design and Methods: Not to exceed
three pages.
H. Consortium/Contractual Arrangements: Not to
exceed one-half page.
I. Literature Cited: Not to exceed one page.
Section 3. Appendix: Optional.
Submit the original application and four copies to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
Mail 2 exact copies of the application and 2 sets of
appendices (appendices are optional) to:
Dr. Sally Mulhern
AIDS Review Section
Program and Project Review Branch
National Institute of Allergy
and Infectious Diseases
Westwood Building, Room 3A12
Bethesda, MD 20892