Full Text PA-95-021

MODELS FOR AIDS AND AIDS-RELATED MALIGNANCIES

NIH GUIDE, Volume 24, Number 2, January 20, 1995

PA NUMBER:  PA-95-021

P.T.


Keywords: 


National Cancer Institute
National Institute of Allergy and Infectious Diseases

PURPOSE

This Program Announcement (PA) is a joint effort by the National
Cancer Institute (NCI) and the National Institute of Allergy and
Infectious Diseases (NIAID) to encourage investigators to develop
useful and predictive biochemical, cellular, and in vivo models that
could be used for the preclinical evaluation of new therapies against
HIV disease and AIDS-related malignancies.  The development of well-
characterized in vitro and in vivo models would accelerate and
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 AIDS 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 "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

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 may be submitted from one institution or may include
arrangements with several institutions, if appropriate.  Applications
involving minority institutions are encouraged.  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.

MECHANISM OF SUPPORT

Support for the PA will be by the investigator-initiated research
project grant (R01), FIRST (R29) award, or the Interactive Research
Project Grants (IRPG) mechanisms.  If an IRPG is proposed, it must
consist of a minimum of two independent applications (see PA-94-086,
NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29, 1994).
An IRPG may consist of a combination of R01s and R29s or R01s only,
but may not consist solely of R29 applications.  An IRPG may also
contain shared interactive resources (Cores), which must serve at
least two of the research projects in order to facilitate achievement
of the Group's common research goals.  Collaborative arrangements
involving more than one institution are especially encouraged,
including participation of the pharmaceutical industry where
appropriate.

FUNDS AVAILABLE

The NCI has set aside approximately $2.0 million total costs in
Fiscal Year 1995 for the first year of funding and NIAID will give
special consideration for 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, and in vivo models
that could be used 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.  Although the NCI and NIAID have a
continuing interest in the research areas of this PA, the latest
anticipated award date with set aside funds is September 30, 1995.

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 immunodeficiency
syndrome (AIDS), no cure has been identified for AIDS or AIDS-related
malignancies, including high-grade B cell non-Hodgkin's lymphoma,
Kaposi's sarcoma, Hodgkin's disease, anogenital dysplasia and cancer,
and basal cell carcinoma.  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, and in vivo models that could be
used 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.

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.  Since
considerable effort is being expended on reverse transcriptase and
proteases, applications on these enzymes are not encouraged for this
initiative.  However, applicants should consider high volume screens
which would accommodate the needs of combinatorial chemistry
programs.  For those AIDS-related cancers in which a putative
cofactor may be involved, 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 AIDS pathogenesis and are simpler, safer and less
expensive than currently available models are urgently needed for the
evaluation of therapies for AIDS and AIDS-related malignancies.
Novel approaches using transgenic and gene knockout animals are
especially encouraged.  While the use of small animals such as mice
is most practical because of their availability and low cost, other
animal models can be proposed.  However, non-lentivirus models are
not encouraged.  For the models of both AIDS 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.

Applicants are reminded to provide a rationale for their model; to
justify and perhaps demonstrate its potential utility over existing
models, if applicable; and to provide a research plan involving a
testable hypothesis.  Relevance to the in vivo disease state,
reproducibility and other important parameters of the assay should be
documented using appropriate statistical analysis.

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. 9/91) 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, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/435-0714.  The title and number of the announcement must be typed
in Section 2a 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.

If an IRPG is proposed, each application must be identified along
with the number of the PA and the phrase "Investigator-initiated
IRPG."  All R01 or R29 applications constituting the proposed IRPG
cohort must be submitted in a single package, whether or not the
applications arise from the same institutions.  For detailed
instructions for preparation and submission of IRPG applications,
refer to PA-94-086, NIH Guide for Grants and Contracts, Volume 23,
Number 28, July 29, 1994.

The complete original application and five legible copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH, in accordance with the standard NIH peer review
procedures.  Following scientific-technical review, the applications
will receive a second-level review by an appropriate national
advisory board/council.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified.

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.  For Fiscal Year 1995, the NCI has set aside $2 million
for this initiative.  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 Boulevard 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
National Cancer Institute
Executive Plaza North, Room 832
6130 Executive Boulevard 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 242
6120 Executive Boulevard MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, Ext. 231
FAX:  (301) 496-8601
Email:  MICHELLE BURR@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 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health System Agency review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non- use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

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