kristoff@GENBANK.BIO.NET (Dave Kristofferson) (02/23/90)
NIH GUIDE - Vol. 19, No. 7, February 16, 1990 - Page 14
FULL TEXT OF RFAs FOR ONLINE ACCESS
REQUEST FOR RESEARCH GRANT APPLICATIONS:RFA
RFA: 90-HL-07-B
THROMBOCYTOPENIC PURPURA IN HIV INFECTION
P.T. 34, FF, II; K.W. 0715008, 0785070, 0710070, 1003018, 1002004
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Application Receipt Date: September 14, 1990
PURPOSE
The Division of Blood Diseases and Resources, National
Heart, Lung, and Blood Institute (NHLBI), invites grant applications
for a single competition for support of basic and applied
research on the pathophysiology of thrombocytopenias in
persons infected with Human Immunodeficiency Virus (HIV) as
well as to determine safe and effective treatment for the
thrombocytopenias.
DISCIPLINES AND EXPERTISE
Among the disciplines and expertise that may be appropriate
for this program are platelet biochemistry, hematology,
immunology, cell biology and virology.
ADMINISTRATIVE BACKGROUND
The Division of Blood Diseases and Resources (DBDR) designs
and administers programs for research in hematology and
transfusion medicine. The Blood Diseases Branch, DBDR, is
responsible for supporting a broad spectrum of basic and
clinical research programs in hemostasis and thrombosis.
Understanding the basic mechanisms involved in the normal
functions of platelets and how they go awry in pathological
conditions are goals important to NHLBI.
SCIENTIFIC BACKGROUND
Several hematologic disorders may coexist with the acquired
immunodeficiency syndrome (AIDS). Cytopenias as well as
hemostatic derangements have been described in patients in
both early and advanced stages of HIV infection. An
autoimmune thrombocytopenia was described in 1982. It is now
recognized that immune thrombocytopenic purpura (ITP) in an
asymptomatic carrier may signal the onset of clinical
disease. Recently, several cases of thrombotic
thrombocytopenic purpura (TTP), generally regarded as a rare
disease, have been described in association with HIV
infection along with a reported case of TTP associated with
HTLV-1 infection.
ITP is a disease caused by
immunologically mediated platelet destruction. ITP
frequently accompanies HIV infection. Clinically, ITP may be
associated with hemorrhage in AIDS patients whose platelet
count falls below 50,000/ul. The etiology of HIV-related
ITP is complex and is thought to be related to a variety of
factors such as infection, splenomegaly, and suppression of
hematopoiesis by HIV in addition to the immunologic
destruction of platelets. Increased platelet destruction by
an immune mechanism probably occurs in most HIV-infected
patients but it has not been well characterized nor has
therapy been adequately investigated.
Increased platelet-associated antibody is present in most
HIV-infected persons but its relationship to increased
platelet destruction is not at all clear. In ITP, not
associated with HIV infection, the amount of platelet-
associated IgG does not always correlate with the severity
of platelet destruction. In HIV-infected individuals, the
type of antibody bound to the platelet surface may vary with
the clinical characteristics of the HIV-positive group under
study. Platelet-associated IgG in HIV-infected hemophiliacs
with ITP has been identified as a 7S platelet-reactive IgG
capable of reacting with both homologous and autologous
platelets. The presence of the 7S antibody on platelets
appears unrelated to simple passive absorption due to
hypergammaglobulinemia. There appears to be an inverse
correlation between the level of platelet-associated
antibody and platelet count. By contrast, HIV-infected
narcotic addicts and homosexuals with ITP demonstrate no
such inverse relationship and characterization of platelet-
associated antibody has yielded different results. In
infected homosexual men, an autoantibody directed against a
25,000 dalton platelet membrane antigen present on normal
platelets can be eluted from the platelet surface. In
infected narcotic addicts, ITP may be related to adsorption
of immune complexes to the platelet surface followed by
accelerated destruction of the platelet by
reticuloendothelial cells. The characteristics of these
complexes or their relation to viral antigenemia and
associated immune complex formation remain to be defined.
ITP is also found in narcotic addicts who are HIV- negative.
The mechanism of this phenomenon is unknown. The apparent
differences between patient groups deserve full evaluation.
Levels of platelet-associated immunoglobulin in
patients with ITP are higher in those with HIV infection
than in those who are uninfected with HIV. In infected
hemophiliacs, concentrations of associated immunoglobulin
are 3 to 4 times greater than those found in classic ITP.
However, non-thrombocytopenic HIV-infected hemophiliacs also
have platelet-associated IgG levels that intermediate
between thrombocytopenic hemophiliacs and individuals with
classical ITP. Although an increased clearance of
radiolabeled red blood cells by the reticuloendothelial
system occurs in HIV-infected individuals, this observation
alone does not fully explain the increase in platelet
destruction: ill patients who have neither HIV infection nor
ITP may display similar increased clearances. It is unclear
why and by what mechanism(s) all three groups of HIV
antibody-positive individuals develop thrombocytopenia, given
their differing immunologic profiles.
Equally problematic is the selection of optimal treatment
for these patients with ITP. Whereas some of these patients
respond to prednisone for the short term, the long-term
effects of these immunomodulative approaches and their
relation to progression of AIDS have not been fully
defined. Patients followed for short periods appear to
suffer no adverse effects from splenectomy and prednisone
treatment; however, a controlled trial with extensive
follow-up will be needed before specific recommendations can
be given. Although intravenous IgG has been found to be
effective, it is extremely expensive and adequate data
concerning long-term use are not available. Treatment
successes have been reported with azothymidine (AZT) but
this drug has not been extensively studied in patients with
AIDS-associated ITP. The mechanism for the purported
benefit of the drug is not known. It has been
suggested that AZT may decrease antigenemia and immune
complex formation or may act in an indirect way by
decreasing the polyclonal B- cell activation which results
from infection with HIV. AZT is known to suppress
hematopoiesis. There is some evidence to suggest that the
mechanism of thrombocytopenia in HIV-infected individuals
differs from the process that damages megakaryocytes and
platelets in classic ITP. Optical and electron microscopic
examination of bone marrow samples from HIV-positive
individuals showed a surprisingly large number of denuded
megakaryocyte nuclei. The ratio of denuded nuclei to intact
megakaryocytes in hematologically normal individuals was
1:81 compared to 1:37 in ITP and 1:5.3 in HIV-positive
individuals. The difference in this ratio between ITP and
HIV marrows was significant with p<0.001. It has been
suggested that HIV-associated injury to megakaryocytes is
different and more extensive than that in ITP. The presence
of a large number of denuded megakaryocyte nuclei in marrow
specimens could be an indication of HIV infection even in
the absence of overt AIDS or thrombocytopenia. Recent in
situ hybridization studies with an HIV RNA probe showed that
the megakaryocyte of all patients examined (10) expressed
viral RNA. Thus, besides the immune mechanism of platelet
destruction, direct infection of megakaryocytes by HIV may
be a factor leading to a decrease in platelet production.
TTP is an unusual syndrome, first described in 1924,
characterized clinically by microangiopathic hemolytic
anemia, thrombocytopenia, neurologic findings, renal
abnormalities, and fever. The pathogenesis(ses) of this
syndrome still remains unknown. TTP and HIV infection are
associated far less frequently than ITP and HIV infection.
However, the association of TTP with HIV infection could be
statistically significant. The fact that this association
is only now being recognized suggests that there may be a
long incubation period for TTP or that the association is a
rare one that is recognized now only because of the increased
number of persons with HIV infection.
Although the pathophysiology of TTP is unknown, it has been
suggested that TTP in AIDS may be attributed to immune
complexes. Some reports suggest that circulating immune
complexes promote microthrombi formation and that the
subsequent endothelial cell damage leads to platelet
adhesion and aggregation and a deficiency of prostacyclin
production. Most patients present with some degree of
vasculitis and endothelial damage of small blood vessels,
suggesting that these conditions may be responsible for the
syndrome in these instances. Other studies suggest the
involvement of platelet agglutinating proteins, abnormal von
Willebrand factor multimers, or calcium-dependent
proteinases. The association of TTP and neoplastic
disorders has been reported infrequently. Both hematologic
malignancy and solid tumors have been described in
association with TTP. Investigators who have reported TTP
in AIDS patients have suggested that the TTP syndrome could
have been triggered by the altered immune system of AIDS or
AIDS-related complex or that TTP may have occurred
independently. Direct tests for immune complexes and
platelet-associated immunoglobulins have not been carried
out in this population of TTP patients; nor has the
possibility been tested that endothelial damage by HIV or other
superimposed viral infections like herpes is the primary
triggering mechanism. Another suggested
mechanism which thus far has been untested is that the
pathophysiology of TTP is related to T-cell dysfunction.
Prior to the institution of plasma exchange for the clinical
treatment of TTP, the disease was more than 80 percent
fatal. Even with plasma exchange, about 25 percent of
patients still die from this fulminant disease. No
standardized therapy other than plasma exchange is generally
agreed on although other treatments, in combination with
plasma exchange, are in use. These include aspirin and
dipyridamole which interfere with platelet function, and
drugs such as vincristine and corticosteroids that are
thought to be effective because of immunosuppressive action.
IgG has been found to be efficacious in a small number of
cases. Plasma infusions without exchange have also been
reportedly effective. TTP of AIDS has been reported to be
successfully treated with "conventional therapy" - plasma
exchange and antiplatelet agents in addition to
corticosteroids.
REFERENCES
Abrams, D., Kiprov, D., Goedert, J., Sarrngardhara, M.,
Gallo, R., Volberding, P., Antibodies to human T-
lymphotropic virus type III and development of the acquired
immune deficiency syndrome in homosexual men presenting with
immune thrombocytopenia. Ann Intern Med. 104: 47, 1986.
Auch, D., Budde, U., Hammerstein, U., Niese, D., Schmidt,
R., Brackmann, H., Dengler, H., FcR-medicated clearance in
thrombocytopenic and non-thrombocytopenic patients with
hemophilia A and possible relation of thrombocytopenia to
HIV seropositivity. Eur J Haematol. 39: 440, 1987.
Ballem, P., Belzberg, A., Doubroff, P., Spurston, B.,
Chambers, H., HIV-associated ITP: Mechanism of the
thrombocytopenia and its response to AZT. IV Internationl
Conf AIDS 7648, 1988.
Dixon, A.C., Kwock, D.W., Nakamura, J.M., Yanagihara, E.T.,
Saiki, S.M., Bodner, A.J., Thrombotic thrombocytopenia
purpura and human T-lymphotrophic virus, Type 1 (HTLV-1).
Ann Intern Med. 110: 93, 1989.
Holtzman, R., Walsh, C.M., Karpatkin, S., Risk for the
acquired immunodeficiency syndrome among thrombocytopenic
homosexual men seropositive for the human immunodeficiency
virus. Ann Int Med. 106: 386, 1987.
Jokela, J., Flynn, T., Henry, K., Thrombotic
thrombocytopenic purpura in a human immunodeficiency virus
(HIV)-seropositive homosexual man. Am. J. Hematol. 25: 341,
1987.
Karpatkin, S., Nardi, M., Immunologic thrombocytopenic
purpura in human immunodeficiency virus-seropositive
patients with hemophilia. Comparison with patients with
classic autoimmune thrombocytopenic purpura, homosexuals
with thrombocytopenia, and narcotic addicts with
thrombocytopenia. J. Lab Clin Med. 111: 441, 1988.
Kurtzberg, J., Friedman, H., Kinney, T., Chaffee, S., Stine,
K., Falletta, J., Weinhold, K., Management of Human
Immunodeficiency Virus-associated thrombocytopenia with
intravenous gamma globulin. J Am Ped Hem Onc. 9: 299, 1987.
Leaf, A.N., Laubenstein, L.J., Raphael, B., Hochster, H.,
Baez, L., Karpatkin, S., Thrombotic thrombocytopenia
purpura associated with human immunodeficiency virus Type
1(HIV-1) infection. Ann Intern Med. 109: 194, 1988.
Morris, L., Distenfeld, A., Amorosi, E., Karpatkin, S.,
Autoimmune thrombocytopenic purpura in homosexual men. Ann
Intern Med. 96: 714, 1982.
Oksenhendler, E, Bierling, P, Farcet, J, Rsbian, C,
Seligmann, M, Clauvel, J., Response to therapy in 37
patients with HIV-related thrombocytopenic purpura. Br J
Hem. 66: 491, 1987.
Oksenhendler E, Bierling P, Ferchal F, Chauvel J, Seligmann,
Zidovudine for thrombocytopenia related to Human
Immunodeficiency Virus infection, Ann Int Med. 110: 366,
1989.
Perkocha, LA, Rodgers GM,. Hematologic aspects of human
immunodeficiency virus infection: laboratory and clinical
considerations, Amer. Journal of Hematology. 29: 94, 1988.
Savona, S, Nardi, M, Lennete, E, Karpatkin, S.,
Thrombocytopenic purpura in narcotics addicts. Ann Int Med.
102: 737, 1985.
Schneider P, Abrams D, Rayner A, Horn D., Immunodeficiency-
associated thrombocytopenic purpura: response to
splenectomy. Arch Surg. 122: 1175,1987.
Shulman R, Leissinger C, Hotchkiss, A, Kautz C., The
nonspecific nature of platelet associated 1gG. Trans Assoc
Am Phy. 160: 213, 1982.
Taaning, E, Scheibel, E, Laursen, B, Ingerslev, J., Pattern
of Immunoglobulin Classes and IgG subclass of platelet-
associated immunoglobulin in HIV-seropositive hemophiliacs.
Vox Sang. 54: 205, 1988.
Termin, C.S., Zucker-Franklin, D., and Cooper, M.C.,
Denuded megakaryocyte nuclei: a manifestation of HIV-
infection regardless of disease progression or platelet
count. Blood. 72: 341a, 1988
Walsh C, Nardi, M, Karpatkin, S. Anti-F(ab)2 antibodies in
thrombocytopenia patients at risk for the acquired
immunodeficiency syndrome. J Clin Invest. 77: 1756, 1986.
OBJECTIVES AND SCOPE
The objective of this initiative is to support basic and
applied research on thrombocytopenic purpura occurring in
conjunction with HIV
infection. The aim is to encourage research that will
increase our understanding of the pathophysiology of
thrombocytopenias, such as immune thrombocytopenic purpura
(ITP) and thrombotic thrombocytopenic purpura (TTP), in HIV-
infected persons as well as to determine safe and effective
treatment for the thrombocytopenia.
The following areas of research would be appropriate for
this RFA:
o elucidation of the mechanism(s) by which ITP is
produced in the HIV-infected individual, status and
mechanism of thrombocytopenia at different stages of HIV
infection, characterization of the platelet-associated
antibody, and its relationship to uptake by the macrophage,
and the severity of the thrombocytopenia;
o correlation of ITP with viral antigenemia and effect
of agents which reduce the antigen load, such as AZT, on the
rate of platelet destruction;
o studies on the properties of megakaryocytes and
platelet production in HIV-infected persons;
o physiological status of the endothelium in HIV-positive
individuals;
o elucidation of the mechanism(s) of TTP in AIDS which
may include studies of T-cell function, role of immune
complex, and other factors such as those producing primary
vascular injury;
o studies to determine whether the pathophysiology of
TTP in HIV-infection differs from that in individuals not
infected with HIV; and
o determination of the efficacy of treatment on platelet
levels, the amount and characteristics of platelet-
associated antibody, immune function, subsequent
development of opportunistic infections and the progression
to AIDS.
These are only examples of the types of research projects
that would be responsive to the goals of this solicitation.
Investigators are encouraged to develop their own innovative
approaches to understand the pathophysiology of
thrombocytopenias in HIV-infected individuals and/or to
treat these serious complicating disorders.
MECHANISM OF SUPPORT
The support mechanism for this five-year program will be the
traditional, individual research grant. Although
approximately $1,200,000 (for direct plus indirect costs)
for this program is included in the financial plans for
fiscal year 1991, award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.
The specific number of awards to be funded
depends 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.
Upon initiation of the program, the Division of Blood
Diseases and Resources will sponsor periodic meetings to
encourage exchange of information among investigators with
research interests in this area. In preparing 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 also should
include a statement in their applications indicating their
willingness to participate in such meetings.
Applicants are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed
research project. However, the maximum award for this
activity is 5 years. At the end of the initial award
period, renewal applications may be submitted for peer
review and competition for support as part of the regular
grant program of the NIH. Although it is anticipated that
support will begin in March 1991,
the first year of any award made in response to an
Institute-solicited program may be for less than the 12-
month recommended period.
All current policies and requirements that govern the
research grant programs of the National Institutes of
Health will apply to grants awarded in connection with 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.
Women and minority individuals should be included in the
study population; otherwise a clear rationale for their
exclusion must be provided in the application. Minority
institutions are encouraged to apply, and other
institutions are encouraged to establish collaborative
arrangements with minority institutions.
REVIEW PROCEDURES AND CRITERIA
Review Method. All applications submitted in response to
this RFA 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. The special ad hoc review group will
be composed of reviewers with special expertise in such
areas as platelet biochemistry, hematology, immunology, and
other areas depending on the content of the applications
received. 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 grant
program of the NIH. If an application submitted in
response to this RFA is identical to one already submitted
to the NIH for review by the Council in the same cycle, the
principal investigator will be asked to withdraw the
pending application before the new one is accepted.
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. Prospective applicants are asked to
submit a one-page letter of intent that includes the
identification of any other participating institutions or
investigators. Such letters are requested for the purpose
of obtaining an indication of the number of applications
to be received, and the NHLBI usually does not
acknowledge their receipt. A letter of intent is not
binding, nor is it a necessary requirement for application.
This letter should be received no later than July 23, 1990
and be sent to:
Charles L. Turbyfill, Ph.D.
Review Branch, Division of Extramural Affairs
National Heart, Lung and Blood Institute
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 an applicant institution's office of sponsored
research. 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 RFA
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 "Thrombocytopenic Purpura in
HIV Infection" and the RFA number NIH-89-HL-7-B.
THE RFA LABEL ENCLOSED WITH THE PHS-398 FORM MUST BE AFFIXED
TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED
APPLICATION. FAILURE TO USE THIS LABEL COULD RESULT IN
DELAYED PROCESSING AND REVIEW OF YOUR APPLICATION.
Application Procedure. Send or deliver the completed
application and four (4) signed, complete photocopies of it
to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
Send 19 additional copies of the application to Dr. Charles
Turbyfill at the address listed under Letter of Intent.
IT IS IMPORTANT TO SEND THESE 19 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 14, 1990. An
application not received by this date will be considered
ineligible.
Timetable.
Letter of Intent July 23, 1990
Application Receipt Date September 14, 1990
Review by the National Heart, Lung and
Blood Advisory Council February 14 - 15, 1991
Anticipated Award Date March 1, 1991
Inquiries. Inquiries regarding this announcement may be
directed to the program administrator:
Pankaj Ganguly, Ph.D.
Blood Diseases Branch
Division of Blood Diseases and Resources
National Heart, Lung and Blood Institute
National Institutes of Health
Federal Building, Room 5A12
Bethesda, MD 20892
Telephone: (301) 496-5911
The programs of the Division of Blood Diseases and
Resources, National Heart, Lung, and Blood Institute, are
identified in the Catalog of Federal Domestic Assistance,
number 13,839. Awards will be made under the authority of
the Public Service Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CRF
Part 74. This program is not subject to the
intergovernmental review requirements of Executive Order
12372, or to Health Systems Agency Review.
REQUEST FOR RESEARCH APPLICATIONS: RFA
RFA: 90-HD/DK-05
GENETIC AND METABOLIC FACTORS IN OBESITY
P.T. 34, AA; K.W. 1002019, 0715135, 0715145, 0403001, 0411005
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Application Receipt Date: June 11, 1990
The Endocrinology, Nutrition and Growth Branch of the Center for
Research for Mothers and Children (CRMC) of the National
Institute of Child Health and Human Development (NICHD), and the
Obesity, Eating Disorders, and Energy Regulation Program of the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invite research grant applications for studies of genetic
and metabolic factors associated with the development of obesity
in childhood, adolescence and adulthood, as well as genetic and
metabolic factors discernible in childhood that predict the onset
of obesity later in life. By issuing this request for
applications (RFA), the NICHD and the NIDDK are encouraging
investigators' interest in a research area important to their
mission.
BACKGROUND:
The increasing prevalence of obesity in this country is a major
public health problem, since obesity is linked to adult onset
(Type II) diabetes mellitus, atherosclerotic cardiovascular
disease (ASCVD), hypertension, and some kinds of cancer. Data
from the Framingham Study show that obesity is a risk factor for
ASCVD independent of other associated risk factors. Therefore,
investigations of the cause and prevention of obesity remain
important research priorities.
Childhood obesity is among the most prevalent of metabolic
disorders affecting the pediatric population in the United
States. The anthropometric data generated by the National Health
and Nutrition Examination Surveys (NHANES) have provided
unequivocal evidence of the increasing prevalence of childhood
obesity. Between 1965 and 1980 the prevalence of obesity
increased by 54 percent among 6-11-year-old children and by 39
percent among 12-17-year-old adolescents.
The prevalence of overweight is generally higher in women than in
men. Among the different ethnic groups studied in the second
NHANES, non-Hispanic white women display the lowest prevalence of
overweight followed by Cuban women. Non-Hispanic black women
have the highest prevalence, and the estimates for
Mexican-American and Puerto Rican women fall between these two
extremes. Among males, non-Hispanic whites have the lowest, and
Mexican-Americans have the highest, prevalences of overweight.
The attendant morbidity of obesity and the limited success of
both dietary and behavioral therapy underscore the need for
better preventive approaches to the problem of obesity in
children, adolescents and adults. Studies of the natural history
of obesity from infancy through adulthood have shown that obesity
at age four or above predicts obesity in adulthood with an
accuracy that increases with age of onset. An important
preventive implication of this finding is that intervention
strategies employed to prevent obesity should be initiated in
childhood.
Abdominal obesity characterized by an elevated waist-to-hip
circumference ratio independent of the degree of obesity has been
found to be a risk factor for stroke, myocardial infarction, and
diabetes mellitus in men. Visceral fat or the proportion of
visceral fat has been found to be related to diabetes and
impaired glucose tolerance and is characteristic of Cushing's
syndrome. A possible explanation for these observations is the
reported increased visceral fat mass in abdominal obesity but not
in general obesity. Increased visceral fat mass could have
detrimental effects by exposing the liver to high concentrations
of free fatty acids with subsequently increased very low-density
lipoprotein (VLDL) secretion and reduced insulin uptake. Other
possible explanations relate to the differing metabolic activity
within fat cells in the waist and abdomen compared to those in
the thigh and buttock. Little is known about the developmental
history of fat distribution during childhood and adolescence that
results in elevated waist/hip girth ratios, nor is there much
information about the genetic or metabolic mechanisms that
determine adipose tissue distribution.
Studies on monozygotic and dizygotic twins demonstrate a
significant genetic influence on an individual's total fat mass,
subcutaneous fat distribution and subcutaneous fat to total fat
mass ratio. There is also a significant genetic influence on fat
deposition and fat distribution when individuals ingest extra
calories. Consequently, there may be considerable differences in
the sensitivity of different phenotypes of obesity to changes in
life styles or environmental conditions. Although obesity is
common in all ethnic groups, the majority of clinical studies
investigating the mechanisms for the development of obesity and
the metabolic and health consequences associated with obesity
have been conducted in white populations. In order to promote
appropriate health messages and recommendations for non-whites,
the similarities and differences among various ethnic populations
need to be studied.
A crucial research issue being addressed by the NICHD and the
NIDDK concerns the genetic and metabolic antecedents of obesity
in childhood, adolescence and adulthood. The ultimate goal is to
discover genetic and metabolic markers of the pre-obese state in
order to identify those individuals at high risk of becoming
obese and to design preventive programs to meet their needs.
Such biological markers could be genes or gene products or
abnormal responses to particular stimuli. Successful prevention
of obesity in childhood should reduce its prevalence and
associated morbidity in adulthood. Reliable methods of detecting
those children at greatest risk for obesity are needed in order
to prevent its onset, and better methods of prevention are needed
for those at high risk.
RESEARCH GOALS:
The primary focus of this RFA is to identify genetic and
metabolic markers in children, adolescents and adults that
predict the development of obesity. Recent evidence points to a
genetic component of variations in energy expenditure and implies
that a tendency to obesity is a consequence of increased
efficiency of energy storage or conservation. Thus, analyses are
needed of the basis for individual differences in energy
expenditure for basal metabolic rate, thermic effect of food and
activity. The identification of genetic components of energy
metabolism in childhood could lead to the development of robust
predictors of obesity in certain individuals and families.
Linkage studies of candidate genes contributing to obesity should
be performed in families predisposed to severe obesity and in
animal models of hereditary obesity. Animal models may be useful
for intensive metabolic studies of the pre-obese state in fetal
and neonatal life. A search should be made of the central
nervous system and hypothalamic-pituitary axis in these animals
for neurohumoral factors leading to obesity.
An elevated waist/hip girth ratio in adults is a marker for
increased susceptibility to atherosclerotic cardiovascular
disease. It remains to be determined if this relationship has a
genetic basis, and when in childhood or adolescence the
association can first be detected. Developmental relationships
between an elevated waist/hip girth ratio, abdominal fat, and
insulin resistance in childhood, adolescence, and adulthood need
to be clarified. Correlations are needed in these age groups
between the waist/hip girth ratio and the basal insulin levels
and areas under the glucose and insulin curves following oral
glucose tolerance tests. The relative contributions in these age
groups of intra-abdominal and subcutaneous abdominal fat to the
increased risk need to be ascertained.
Since most data available for humans apply to whites,
predominantly to adult white males, data on similarities as well
as differences characterizing obese states among populations of
different gender and ethnic background are needed. Differences
in the mechanism leading to the development of obesity, including
regional distribution of adipose tissue among subjects of
different age, gender and ethnic origin, are important to
ascertain and may be associated with different biological or
genetic markers.
INCLUSION OF MINORITIES IN STUDY POPULATIONS
Applicants are urged to give added attention (where
feasible and appropriate) to the inclusion of minorities
in study populations for research into the etiology of
diseases, research in behavioral and social sciences,
clinical studies of treatment and treatment outcomes,
research on the dynamics of health care and its impact
on disease, and appropriate interventions for disease
prevention and health promotion. If minorities are not
included in a given study, a clear rationale for their
exclusion should be provided.
INCLUSION OF FEMALES IN STUDY POPULATIONS
Applicants are urged to consider the inclusion of
females in study populations for all clinical
research efforts. Exceptions would be studies of
diseases which exclusively affect males or where
involvement of pregnant women may expose the fetus to
undue risks. Gender differences should be noted and
evaluated. If females are not to be included, a clear
rationale should be provided for their exclusion.
In order to provide more precise information to the
treatment community, it is recommended that publications
resulting from
research in which the
study population was limited to one sex for any reason
other than that the disease or condition studied
exclusively affects that sex, should state, in the
abstract summary, the gender of the population studied,
e.g., "male patients," "male volunteers," "female
patients," "female volunteers."
MECHANISM OF SUPPORT:
Applications in response to this RFA will be funded through the
traditional individual research award program of the NICHD and
the NIDDK. This announcement is for a single competition with
the application receipt deadline of June 11, 1990. The earliest
possible start date for grants is April 1, 1991. It is
anticipated that eight (8) grants will be awarded under this
program, contingent upon receipt of a sufficient number of
meritorious applications and the availability of funds.
REVIEW PROCEDURES AND CRITERIA:
Applications will be reviewed by NICHD and NIDDK staff for
responsiveness to the RFA. Applications judged to be
nonresponsive will be returned. The applicant may resubmit the
application and have it assigned for review in the same manner as
unsolicited grant applications. An application will be
considered nonresponsive to this RFA if it is identical to one
already submitted to the NIH for review, unless the previous
application is withdrawn.
Responsive applications may be subjected to a triage by a
peer-review group to determine their scientific merit relative to
the other applications received in response to this RFA. 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 evaluated for scientific/technical merit by a
group review convened solely for this purpose by the Scientific
Review Program, NICHD. Criteria for the initial review include
the significance and originality of research goals and
approaches; the feasibility of research and adequacy of the
experimental design; the research experience and competence of
the investigator(s) to conduct the proposed work; the adequacy of
investigator effort devoted to the project; and the
appropriateness of the project duration and cost relative to the
work proposed. Following review by the Initial Review Group,
applications will be evaluated by either Institute's Advisory
Council for program relevance and policy issues before awards for
meritorious proposals are made.
APPLICATION PROCEDURE:
Applications should be submitted on Form PHS 398 (rev. 10/88),
available in business or grants offices at most academic research
institutions or from the Division of Research Grants, NIH. The
phrase PREPARED IN RESPONSE TO RFA 90-HD/DK-05 GENETIC AND
METABOLIC FACTORS IN CHILDHOOD OBESITY should appear in item 2 of
the face page. The RFA label available in the 10/88 version of
Form PHS 398 must be affixed to the bottom of the face page.
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. The original and four (4) copies are to be
sent no later than June 11, 1990 to:
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
In addition to the copies sent to the Division of Research
Grants, two (2) copies of the application should be sent to:
Laurance Johnston, Ph.D.
Scientific Review Program
National Institute of Child Health
and Human Development
Executive Plaza North, Room 520A
Bethesda, MD 20892
Any inquiries about this RFA should be directed to:
Gilman D. Grave, M.D
Chief, Endocrinology, Nutrition
and Growth Branch
Center for Research for Mothers and Children
National Institute of Child Health
and Human Development
Executive Plaza North, Room 637
Bethesda, MD 20892
Telephone: (30l) 496-5593
or
Van S. Hubbard, M.D., Ph.D.
Director
Obesity, Eating Disorders,
and Energy Regulation Program
National Institute of Diabetes
and Digestive and Kidney Diseases
Westwood Bldg Room 3A18
Bethesda, MD 20892
Telephone: (30l) 496-7823
This program is described in the catalog of Federal Domestic
Assistance No. 13.865, Research for Mothers and Children.
Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC241), and administered under
PHS grant policies and Federal Regulations 42 CFR Part 52
and 45 CFR Part 74. This program is not subject to review
by a Health Systems Agency.
This program is described in the catalog of Federal Domestic
Assistance No. 13.848, Digestive Diseases and Nutrition. Awards will
be made under the authority of the Public Health Service Act, Title
III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and
administered under PHS grant policies and Federal Regulations most
specifically at 42 CFR Part 52 and CFR Part 74; this Executive
Order 12372 or Health Systems Agency review.
REQUEST FOR APPLICATIONS
RFA NUMBER: 90-CA-09
RFA TITLE: New Approaches to Understanding Transformation
by SV40 Virus, Polyomaviruses and Adenoviruses
P.T. 34; K.W. 1002019, 1002045, 0755020, 0785140
NATIONAL CANCER INSTITUTE
LETTER OF INTENT RECEIPT DATE: June 15, 1990
APPLICATION RECEIPT DATE: August 24, 1990
INTRODUCTION
Simian virus 40 (SV40), mouse polyomavirus and adenovirus
are DNA tumor viruses that are important model systems
in the study of virally induced tumors in susceptible
animals and the transformation of cells in culture. The
primary cause of these neoplastic events is the introduction
into cells of viral transforming genes that encode viral
oncoproteins (SV40/polyoma T-antigens and adenovirus E1
proteins). The transformation mechanism of these viruses is
unknown, but recent evidence suggests that it
is mediated by interactions with
cellular proteins. Support for this model comes from the
discovery of strong binding interactions between viral
oncoproteins and cellular proto- and anti-oncogene products.
The first such association to be identified was the complex
between middle T-antigen of polyomavirus and the product of
the c-src proto-oncogene. More recently, the large
T-antigens of SV40 and polyomavirus and the E1A protein of
adenovirus each were shown to form complexes with the
product of the Rb anti-oncogene (the retinoblastoma tumor
suppressor gene). Current research is focused primarily on
the interactions of these viral oncoproteins and cellular
genes. However, cellular transformation is a complex
mechanism involving many different metabolic and regulatory
pathways in addition to the cellular processes associated
with the Rb, p53 and c-src proteins. The goal of this
Request for Applications (RFA)
is to stimulate research on the interaction of viral
oncoproteins with other cellular proteins that also may
play a role in transformation.
The present RFA is for a single competition with deadlines
of August 24, 1990 for receipt of applications and June 15,
1990 for receipt of letters of intent.
BACKGROUND
In order to assess the significance of interactions of
T-antigens with cellular proteins, the Biological
Carcinogenesis Branch, DCE, sponsored a workshop on April
17-18, 1989 entitled, "T-Antigens and Proto-oncogene
Interactions." In addition to new data on c-src and Rb
protein interactions, evidence was presented that indicated
that the p53 protein, another cellular protein which
associates with the SV40 large T-antigen and the adenovirus
E1B protein, possessed the properties of a cellular
anti-oncogene. A correlation also was demonstrated between
some human bone and lung cancers and mutations that
inactivate cellular Rb or p53 genes. The discovery of
the associations of viral oncoproteins with the Rb, p53, and
c-src proteins provides a parallel between DNA tumor
virus-induced transformation and comparable transformation
produced by the spontaneous mutation of cellular proto- and
anti-oncogenes in human cancers. Both viral and spontaneous
transformations appear to alter cellular processes that
regulate cell growth and phenotype through changes in the
levels or activities of specific cellular proteins. Thus,
transformation of cells by SV40, polyoma and adenoviruses
should provide excellent, highly manipulable model systems
to study many aspects of the carcinogenic process that have
direct relevance to human cancer.
The workshop participants noted that the full potential of
these model systems to investigate mechanisms related to
human carcinogenesis has not yet been realized. Current
research is focused primarily on interactions of viral
oncoproteins with the Rb, p53 and c-src proteins and their
associated cellular processes. However, cellular
transformation is a complex mechanism involving many
different metabolic and regulatory pathways in addition to
the cellular processes associated with the Rb, p53 and c-src
proteins. Recent evidence suggests that T-antigens and the
E1 proteins may interact with a number of other cellular
proteins, implying that a number of additional regulatory
processes could be altered by these oncoproteins. Although
knowledge of all these processes will be required for a
full understanding of the mechanisms of transformation,
there are few laboratories studying any of the other viral
oncoprotein/cellular protein interactions. Among the prime
candidates for investigation are the T-antigen associations
with the 85kD phosphatidyl inositol kinase and with the 63kD
and 36 kD subunits of protein phosphatase type 2A; and the
as yet uncharacterized 27-29 kD proteins. New approaches
may be needed to investigate the functions of these cellular
proteins or the effects of second messengers (such as the
unusual phosphatide produced by the 85 kD kinase). There is
also a need to develop techniques to identify new cellular
proteins that associate with viral oncoproteins, but that
are not detected by current immunoprecipitation methods.
Based on the known similarities between DNA tumor virus
transformation and some human cancers, workshop participants
strongly recommended expanded studies of viral
oncoprotein/cellular protein interactions as model systems
to gather additional molecular insights into the development
of cancer in man.
RESEARCH GOALS AND SCOPE
The major goal of this RFA is to stimulate research
leading to an understanding of SV40, polyomavirus, and
adenovirus transformation of cells in terms of the cellular
processes that are altered by viral oncoproteins. The
scope of this RFA includes studies of SV40, polyomaviruses
(including BK virus and JC virus) and adenoviruses.
Functional studies of viral oncoprotein-cellular protein
complexes are encouraged. Studies on the Rb, p53, and
c-src interactions with oncoproteins should not be the focus
of the proposed studies since they already are being
extensively studied (Applications focusing only on these
will be considered unresponsive to the RFA and returned to
the investigator.) Where appropriate, some experiments dealing
with these cellular proteins may be included for comparisons
or to extend mechanistic ideas involving several cellular
proteins. Examples of research objectives (which are
not all inclusive) that may be supported under this RFA are:
1) investigations of the impact of viral
oncoprotein/cellular protein complexes on elements of
cellular regulation related to transformation such as (but
not limited to) second messenger regulation, cell cycle
control, transactivation of cellular protein synthesis, and
alteration of plasma membrane properties (e.g., contact
inhibition); 2) development and application of new
approaches to understand the regulatory activities of
pertinent cellular proteins and second messenger molecules
and assessment of the role of these processes in cellular
transformation; 3) functional and structural
characterization of cellular proteins that bind to viral
oncoproteins; 4) development and application of new
techniques and reagents to identify and characterize
additional cellular proteins that bind to viral
oncoproteins.
Where appropriate, collaborative arrangements to facilitate
the achievement of research goals should be considered.
MECHANISM OF SUPPORT
This RFA will use the traditional National Institutes of Health (NIH)
research project (RO1). Responsibility for the planning, direction
and execution of the proposed project will be solely that of
the applicant. Except as stated in this RFA, awards will be
administered under PHS grants policy as stated in the Public
Health Service Grants Policy Statement, DHHS Publication No.
(OASH) 82-50,000, revised January 1, 1987.
Approximately $750,000 in total costs per year for five (5)
years will be committed specifically to fund applications
that are submitted in response to this RFA.
The funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.
The total project period for applications submitted in
response to the present RFA should not exceed five (5)
years. The earliest feasible start date for the initial
awards will be April 1, 1991. Although this program is
provided for in the financial plans of the National Cancer
Institute (NCI), award of grants pursuant to this RFA is
also contingent upon the availability of funds for this
purpose. Non-profit and for-profit institutions, and
foreign as well as domestic institutions, are eligible to
apply.
This RFA is a one-time solicitation. Generally, future
unsolicited competing renewal applications will compete as
research project applications with all other investigator-
initiated applications and be reviewed in a standing
Division of Research Grants study section. However, should
the NCI determine that there is a sufficient continuing
program need, NCI may announce a request for renewal
applications.
REVIEW PROCEDURES AND CRITERIA
REVIEW PROCEDURE
Upon receipt, applications will be reviewed initially by the
Division of Research Grants for completeness. Incomplete
applications will be returned to the applicant without
further consideration. Evaluation for responsiveness to the
RFA is an NCI program staff function. Applications that
are judged non-responsive will be administratively
inactivated but may be submitted as investigator-initiated
grants at the next receipt date. Questions concerning the
relevance of proposed research to the RFA should be directed
to program staff as described in INQUIRIES.
In cases where the expected number of applications is large
compared to the number of awards to be made, the NIH will
conduct an administrative prereview (triage) to eliminate
those that are clearly not competitive. The NIH will
withdraw from further competition those applications judged
to be noncompetitive and notify the applicant and
institutional business official.
Those applications judged to be both responsive and
competitive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the Division of
Extramural Activities, NCI. The second level of review by
the National Cancer Advisory Board considers the special
needs of the Institute and the priorities of the National
Cancer Program.
REVIEW CRITERIA
Proposals responsive to this competitive solicitation will
be reviewed in accordance with the following criteria:
1. Extent of relevance of the proposed research to the aims
of the RFA, i.e., potential for providing insight on the
transformation mechanisms of SV40 virus, polyomaviruses and
adenoviruses.
2. Scientific merit of the proposed approach, including
the adequacy and quality of the methodological approach and
the research design. Familiarity with the proposed
techniques should be demonstrated, e.g., by the presentation
of preliminary data.
3. Expertise and qualifications of the principal
investigator and proposed staff and/or collaborators to
perform the proposed experiments.
4. Documentation of the adequacy of the facilities and
resources.
The review group will examine critically the proposed budget
and recommend an appropriate budget for each approved
application.
METHOD OF APPLYING
The regular research grant application, form PHS-398
(revised 10/88) must be used in applying for these grants.
These forms are available at most institutional business
offices; from the Office of Grants Inquiries, Division of
Research Grants, National Institutes of Health, Room 449,
Westwood Building, 5333 Westbard Avenue, Bethesda, Maryland
20892; or from the NCI Program Director named below.
The RFA label available in the 10/88 revision of Application
Form 398 must be affixed to the bottom of the face page.
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. In addition, the title of the
RFA and the RFA number should be typed on line 2 of the face
page of the application form.
Submit a signed, typewritten original of the application,
including the Checklist, and four (4) signed, exact
photocopies, in one package to the Division of Research
Grants at the address below. The photocopies must be clear
and single sided.
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
At the time of submission, two (2) additional copies of the
application should also be sent to:
REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Room 848, Westwood Building
5333 Westbard Avenue
Bethesda, MD 20892
Applications should be received by August 24, 1990. If an
application is received after that date, it will be
administratively withdrawn. The Division of Research
Grants will not accept any application in response to this
announcement that is the same as one currently being
considered by any other PHS awarding unit.
Animal and human subject approval clearances should be
submitted with the applications to expedite the review
process.
LETTER OF INTENT
Prospective applicants are asked to submit, by June 15,
1990, a letter of intent that includes a descriptive title
of the proposed research, the name and address of the
principal investigator, the names of other key personnel,
the participating institutions, and the number and title of
the RFA in response to which the application is being
submitted.
Although a letter of intent is not required, is not binding,
and does not enter into the review of subsequent
applications, the information which it contains is extremely
helpful in planning for the review of applications. It
allows NCI staff to estimate the potential review workload
and to avoid possible conflict of interest in the review.
The letter of intent should be sent to:
Dr. Susan B. Spring
Program Director
DNA Virus Studies I
Biological Carcinogenesis Branch
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD 20892
Telephone: (301) 496-4533
INQUIRIES
Written or telephone inquiries concerning the objectives and
scope of this RFA or inquiries about whether or not specific
proposed research would be responsive are encouraged and
should be directed to Dr. Susan B. Spring at the above
address. The program director welcomes the opportunity to
clarify any issues or questions from potential applicants.
This program is described in the Catalog of Federal Domestic
Assistance No. 13.393, Cancer Cause and Prevention Research.
Awards are under authorization of the Public Health Service
Act, Section 301 (c), Public Law 78-410, as amended; 42
U.S.C. 241; the Small Business Innovation Development Act,
Public Law 97-219, and Section 410 as amended by Public Law
99-158, 42 U.S.C. 285; and administered under PHS grant
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.