Full Text PA-96-014
 
MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES
 
NIH GUIDE, Volume 25, Number 1, January 26, 1996
 
PA NUMBER:  PA-96-014
 
P.T. 34

Keywords: 
  AIDS 
  Disease Model 
  Pathogenesis 

 
National Cancer Institute
National Institute of Allergy and Infectious Diseases
 
PURPOSE
 
This Program Announcement (PA) is a reissuance of PA-95-021 with a
similar title, which appeared in the NIH GUIDE, Vol. 24, No. 2,
January 20, 1995.  The purpose of the reissuance is to expand the
scope to include refinement of mathematical models and new paradigms
of HIV pathogenesis.  This PA reflects a continuing joint effort by
the National Cancer Institute (NCI) and the National Institute of
Allergy and Infectious Diseases (NIAID) to encourage
investigator-initiated grant applications for the development of
useful and predictive biochemical, cellular, in vivo and mathematical
models for the preclinical evaluation of new therapies against HIV
disease and AIDS-related malignancies.  The availability of
well-characterized in vitro and in vivo models would accelerate the
pace of evaluation of different paradigms of disease progression and
would facilitate the discovery of successful treatments, including
drugs, vaccines, gene therapy, and immune modulators.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This PA,
Models for HIV Disease and AIDS-Related Malignancies, is related to
the priority areas of human immunodeficiency virus/AIDS and cancer.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications involving minority institutions are encouraged.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards, but may participate in
laboratory programs through subcontract or consortium arrangements.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
Research support mechanisms for this PA are the
investigator-initiated research project grant (R01) and FIRST (R29)
award.  R01 grants provide support for up to five years.  R29 awards
must request support for five years and are limited to $350,000 in
direct costs over the entire project period.  Collaborative
arrangements involving more than one institution are encouraged,
including participation of the pharmaceutical industry where
appropriate.
 
The NCI and NIAID have a continuing interest in the research areas of
the PA and will give special consideration to the support of
applications received in response to this initiative.  The level of
support is dependent on the receipt of a sufficient number and
diversity of applications of high scientific merit and the
availability of funds.  Although the goal of this PA is to stimulate
the development of diverse types of efficient and predictive
biochemical, cellular, in vivo, and mathematical models for the
evaluation of new agents for the treatment of HIV disease and
AIDS-related malignancies, priority will be given to in vivo models
if the number of meritorious applications exceeds funds available.
 
Because the nature and scope of the research proposed in response to
the PA may vary, it is anticipated that the sizes of awards will vary
also.
 
The total project period for applications submitted in response to
this PA may not exceed five years.  The NCI and NIAID have a
continuing interest in the research areas of this PA.
 
RESEARCH OBJECTIVES
 
Background
 
Despite advances in our knowledge of the molecular biology of HIV-1
(human immunodeficiency virus) and HIV-2 and increased understanding
of HIV pathogenesis in the development of acquired immune deficiency
syndrome (AIDS), no cure has been identified for HIV disease or
AIDS-related malignancies, including high-grade B cell non-Hodgkin's
lymphoma, Kaposi's sarcoma, Hodgkin's disease, and anogenital
dysplasia and cancer.  As of mid-1994, the World Health Organization
(WHO) estimated that over four million AIDS cases have occurred
worldwide, and that 16 million people are infected with HIV as the
pandemic continues unabated.
 
Objectives and Scope
 
The goal of this PA is to foster the development of useful and
predictive biochemical, cellular, in vivo and mathematical models for
the evaluation of new therapies against HIV disease and AIDS- related
malignancies.  New relevant and cost-effective models are needed for
various stages of preclinical therapy development, including lead
discovery, lead optimization, and final evaluation of the most
promising candidates for clinical trial.  While progress has been
made with cell-based and mechanism-based screens, such as those for
reverse transcriptase and proteases, many other suitable targets
exist but need to be employed in assays.  There is an urgent need for
simpler, safer, more relevant, and less expensive in vivo models to
assess the in vivo efficacy of potential therapeutic candidates.
 
Exploratory basic research studies on the mechanism of action of HIV
genes, cellular genes involved in HIV gene replication, and gene
products are excluded from this PA.
 
The research scope encourages applications in the following areas,
which are illustrated by but not limited to the examples provided:
 
o  Biochemical Assays.  Rapid, resource efficient, and cost effective
assays to block steps in HIV virus replication are encouraged.
Models for well-studied targets such as reverse transcriptase and
proteases are not advocated, whereas models for promising new targets
such as the nef protein are encouraged.  Applicants should consider
high volume screens that would accommodate the needs of combinatorial
chemistry programs.  For those AIDS-related cancers in which a
putative cofactor may be involved, such as the Kaposi's
Sarcoma-Associated Herpesvirus (KSHV), approaches are sought to
identify and define the precise role of the cofactor in the specific
malignancy and to exploit this information for therapeutic advantage.
 
o  Cell Culture Assays.  It is desirable that new cell culture models
be developed for HIV replication and AIDS-related malignancies that
more closely simulate the in vivo state.  For example, models that
mimic the three dimensional, multicellular environment or those based
on single cycle replication kinetics would be of utility.  For
AIDS-related cancers, cell culture systems predictive of in vivo
events that allow for studies of the mechanism(s) of action of
specific cofactors and that would be useful for evaluating potential
therapies are highly encouraged.
 
o  In Vivo Models.  Models that reflect the current state of
knowledge of HIV pathogenesis and are simpler, safer, more relevant
and less expensive than currently available models are urgently
needed for the evaluation of therapies for HIV disease and AIDS-
related malignancies.  Novel approaches using transgenic and gene
knockout animals are especially encouraged.  Although the use of
small animals such as mice is most practical because of their
availability and low cost, other animal models may be proposed.
However, non-lentivirus models are not encouraged.  For the models of
both HIV disease and AIDS-related malignancies, the development of
valid surrogate endpoints for survival is favored in the interest of
conserving resources and reducing assay time and animal discomfort.
 
o  Mathematical Models.  Refinement of mathematical models for viral
levels, CD4+T cell counts, etc. that can be used as predictors of
therapeutic efficacy and in conjunction with clinical studies will be
considered.  New paradigms of HIV pathogenesis that can provide
alternative treatment strategies are encouraged.
 
Applicants are reminded to provide a rationale for their model; to
justify and demonstrate its potential utility over existing models,
if applicable; to provide a research plan involving a testable
hypothesis; and to use the model to demonstrate its utility.
Relevance to the in vivo disease state, reproducibility using
appropriate statistical analysis, and other important parameters of
the assay should be documented.
 
Although the intent of this PA is to restrict studies to those which
are preclinical, clinical specimens may be used whenever required for
the appropriate development of in vitro and animal models.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), 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 28, 1994 (FR 59 14508-14513) 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.
 
APPLICATION PROCEDURES
 
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.  Receipt dates for
applications for AIDS-related research are January 2, May 1, and
September 1.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 6701 ROCKLEDGE DR MSC 7910, BETHESDA MD 20892-7910,
telephone 301-435-0714.  The title and number of the program
announcement must be typed in Section 2 on the face page of the
application.
 
FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE SUITE 1040 MSC 7710
BETHESDA MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete will be
evaluated for scientific and technical merit by study sections of the
Division of Research Grants, NIH, 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
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. Nava Sarver
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C01
6003 EXECUTIVE BLVD MSC 7620
BETHESDA MD 20892-7620
Telephone:  (301) 496-8197
FAX:  (301) 402-3211
Email:  ns18p@nih.gov
 
Dr. Mary K. Wolpert
Division of Cancer Treatment, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Room 832
6130 EXECUTIVE BLVD MSC 7450
BETHESDA MD 20892-7450
Telephone:  (301) 496-8783
FAX:  (301) 496-8333
Email:  mkwolper@helix.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B25
6003 Executive Boulevard, MSC 7610
BETHESDA MD 20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  ju3a@nih.gov
 
Ms. Michelle Burr
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
6120 EXECUTIVE BLVD MSC 7150
BETHESDA MD 20892-7150
Telephone:  (301) 496-7800, Ext. 231
FAX:  (301) 496-8601
Email:  BURRM@GAB.NCI.NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.395, Cancer Treatment Research and 93.856,
Microbiology and Infectious Diseases Research.  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 45 CFR Part 74 and 45 CFR Part 92.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health System Agency review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103- 227, The Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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