Full Text PA-96-066
NIH GUIDE, Volume 25, Number 24, July 19, 1996
PA NUMBER:  PA-96-066
P.T. 34

  Blood Diseases 
  Biology, Cellular 

National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung, and Blood Institute
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI)
invite grant applications for support of research addressing
fundamental questions of hematologic abnormalities exhibited by
humans infected by Human Immunodeficiency Viruses (HIV), the
infectious agents of Human Acquired Immunodeficiency Syndrome (AIDS).
Hematologic abnormalities in patients with the HIV infection are
common.  These abnormalities can significantly impact on the course
of treatment for thesepatients.
Fundamental progress has been made in the understanding of the
molecular biology and clinical aspects of retroviral infection.  It
has become clear that further studies of retroviral-induced neoplasms
of immunodeficiency states will continue to provide useful new
information about the cellular and humoral basis of the immune
responses, including the mechanisms leading to hematologic
abnormalities which are seen following HIV infection.  This
announcement is intended to solicit applications for support of
studies on the cellular basis of these hematologic abnormalities.
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity  for setting priority areas.  Potential
applicants may obtain a copy of "Healthy People 2000 (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock
No.017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government. Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.
This PA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) award mechanisms.
Responsibility for planning, direction, and execution of the proposed
project will be solely that of the applicant.  Because the nature and
scope of the research proposed in response to this PA may vary, it is
anticipated that the size of an award will vary also; however, the
support of requests exceeding the NIDDK average grant size of
$160,000 direct cost for R01 grants would be unusual and require
ample justification.  FIRST (R29) awards are limited to $350,000
direct cost over the five year period.
The objective of this program announcement is to solicit proposals in
which the hematologic abnormalities seen following HIV  infection are
examined at the cellular and molecular level.  Particular
encouragement is offered to investigators who are well-trained in the
modern techniques of cell biology and molecular biology who currently
may be pursuing other research interests.  Investigators with
interdisciplinary and collaborative arrangements already in place are
encouraged to respond to this announcement.  Applications should be
focused on issues directly relevant to the understanding of the
pathogenesis of cytopenia following HIV infection, and the role of
hematopoietic precursor cells in the development of AIDS.  Following
is a description of the types of areas that may be appropriate to
study.  These descriptions are for illustrative purposes only and are
not meant to be all inclusive or restrictive.
Numerous hematologic abnormalities arise in individuals following HIV
infection.  Understanding how these abnormalities arise may be
complicated by a variety of other infections, in addition to HIV,
which usually are seen in these patients.  Bone marrow dysplasia,
anemia, thrombocytopenia, and leukopenia occur frequently in patients
with HIV infection.  Both ineffective hematopoiesis and peripheral
destruction of blood cells may lead to cytopenia common in AIDS
patients.  The latter condition may be due to accelerated utilization
and destruction of cells due to opportunistic infections,
reticuloendothelial cell dysfunction, or to specific autoimmunity.
Ineffective hematopoiesis in patients with AIDS has several potential
causes which may include for example: (1)suppressive effects of
infections; (2) the formation of circulating inhibitors; and (3) the
effects of HIV on hematopoietic stem cells.  The recent development
of new technologies to make recombinant human hematopoietic growth
factors has made it possible to correct some of the cytopenias
associated with HIV infection and has also fostered studies of the
role of growth factors in hematopoiesis, both in vitro and in vivo.
Thrombocytopenia is seen in HIV infected patients with a high degree
of incidence, and immune thrombocytic purpura has been recognized as
a diagnostic category of the AIDS-Related Complex (ARC).  The
development of thrombopenia in HIV infections appears to be similar
to that of other forms of idiopathic thrombocytopenic purpura.
Antibody production against a 25,000 dayton protein of platelet
membrane origin has been postulated to have a resemblance to an HIV
precursor protein and may be involved in the formation of immune
complexes which result in platelet destruction. Anemia is frequently
present in HIV patients and its origin is unknown.  The lack of
reticulocyte response seen in these patients may be due to a
hypoproliferative anemia or to ineffective hematopoiesis.  Low
erythropoietin levels and associated abnormalities seen in some AIDS
patients may be a contributing factor to anemia.
Neutropenia in AIDS patients is common.  The recombinant human growth
factor GM-CSF has been used in some clinical trials with AIDS
patients and has been found to ameliorate the neutropenia of AIDS as
well as that induced by treatment with zidovudine.
Applications for support of clinical studies in humans are  not
requested at this time.  In addition, the following studies would be
considered unresponsive to this program announcement: (1) studies
that do not emphasize the cellular and molecular basis of abnormal
hematopoietic differentiation in AIDS; (2) general studies on
hematopoiesis; and (3) phenomena associated with hematopoiesis in
various disease states not related to AIDS.  Program project grant
applications (P01) are not suited to this program announcement.
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research. This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 1450814513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Investigators are encouraged to consider alternative methods and
approaches in their research grant applications that do not require
the use of whole animals, use alternative species such as nonmammals
or invertebrates, reduce the number of animals required, and
incorporate refinements to procedures that will result in the
elimination or further minimization of pain and distress in animals.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email: asknih@odrockm1.od.nih.gov.
The program announcement title and number must be typed on line 2 of
the face page of the application form and the YES box must be marked.
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
Potential R29 applicants should refer to the announcement on Just-in-
Time Procedures for FIRST and Career Awards (NIH Guide for Grants and
Contracts, Vol. 25, No. 10, March 29, 1996) for information on recent
changes in guidelines for FIRST award format.
The completed original application and five legible copies must be
sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with NIH peer
review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.
Review Criteria
o  scientific, technical, or medical significance and originality of
proposed research;
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
o  availability of the resources necessary to perform the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.
For Applications from Foreign Organizations:
o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or that provide augmentation of
existing U.S. resources.
Applications assigned on the basis of Public Health Service referral
guidelines will compete for available funds with other approved
applications assigned to the National Institute of Diabetes and
Digestive and Kidney Diseases or the National Heart, Lung, and Blood
Institute.  The following will be considered in making funding
o  Quality of the proposed project as determined by peer review;
o  Availability of funds;
o  Program priority.
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome. Direct inquiries
regarding programmatic issues to:
Ralph L. Bain, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AS-19B MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  Ralph_Bain@nih.gov
Helena O. Mishoe, Ph.D.
Division of Blood Diseases and Resources
Nation Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10156
Bethesda, MD 20892-7950
Telephone: (301) 435-0050
FAX:  (301) 480-0868
Email:  hm31y@nih.gov
Inquiries regarding fiscal matters may be directed to:
Trude Hillard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AN-44J, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8859
Email:  HillardT@ep.niddk.nih.gov
Jane Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7174
Bethesda, MD 20892-7924
Telephone:  (301) 435-0166
Email:  davisj@gwgate.nhlbi.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74. This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products. In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children. This is consistent with PHS
mission to protect and advance the physical and mental health of the
American people.

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