BASIC RESEARCH IN SUPPORT OF TREATMENTS FOR AIDS

NIH GUIDE, Volume 22, Number 43, November 26, 1993



PA NUMBER:  PA-94-014



P.T. 34



Keywords:

  AIDS 

  Biomedical Research, Multidiscipl 



National Institute of General Medical Sciences

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Allergy and Infectious Diseases



PURPOSE



The purpose of this program announcement (PA) is to encourage

research in areas fundamental to the development of treatments for

AIDS and associated opportunistic infections.



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,

Basic Research in Support of Treatments for AIDS, is related to the

priority area of HIV infection.  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 foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State or local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are eligible for First Independent Research

Support and Transition (FIRST) (R29) awards and program project (P01)

grants.



MECHANISM OF SUPPORT



Support of this program will be through the individual research

project grant (R01), and the FIRST Award (R29).  Individuals desiring

to apply for support under one of these mechanisms are specifically

encouraged to apply for grants citing this program announcement.



The National Institute of General Medical Sciences (NIGMS) and the

National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) will also support this program through the program project

grant (P01) mechanisms.  However, the National Institute of Allergy

and Infectious Diseases (NIAID) will NOT accept investigator

initiated program project (P01) applications.  Potential applicants

are advised to contact the program staff listed  under INQUIRIES for

guidance in the areas appropriate for program project grant

applications and the preparation of the application itself.



Investigators holding active P01 (NIGMS and NIDDK only), R01, or

Method to Extend Research in Time (MERIT) (R37) grants to study

fundamental processes associated with interaction of proteins with

ligands, bioavailability of drugs, crystallization of proteins,

macromolecular engineering, or evolutionary adaptation, with at least

one year of support remaining at the time of the anticipated award,

are also encouraged to apply through competing supplemental awards.



RESEARCH OBJECTIVES



Despite all that is known about fundamental biological processes,

particularly at the molecular level, and the application of this

knowledge to understanding the structure and replication of HIV,

there are still fundamental gaps in our understanding of basic

biology that must be filled before a rational approach to the

treatment of HIV infection and associated secondary infections can be

accomplished.  These gaps include:



o  A basic understanding of the factors that govern the interaction

of proteins with ligands--especially with respect to the flexibility

of both the binding site of the protein and binding ligand.  Such an

understanding is essential for the de novo design of drugs to inhibit

specific proteins necessary for the HIV life cycle and antibiotics to

treat opportunistic infections.



o  A basic understanding of the factors that govern the availability

of a drug at its site of action.  Potential new drug candidates

frequently fail due to poor bioavailability, i.e., the compounds show

high receptor affinity, but fail to get to their targets in

sufficient quantity.  Recently, efforts to develop HIV protease

inhibitors as new drugs to treat HIV infection have foundered because

of a failure to achieve adequate intracellular drug concentrations.

The reasons why these new drug candidates fail is not well

understood, and thus, cannot be accounted for in the design stage.



o  A basic understanding of the principles that underlie the

crystallization of proteins--especially membrane and/or glycosylated

proteins.  The inability to routinely crystallize a given protein is

a serious roadblock in the determination of the three-dimensional

structure of, for example, the envelope protein of HIV, and other

proteins necessary for the HIV life cycle or proteins important in

the life cycle of organisms that cause opportunistic infections.  The

determination of the structures of these proteins at high resolution

is an essential first step in the design of drugs to inhibit the

processes for which these proteins are essential.



o  A basic understanding of the principles of macromolecular

engineering.  A promising approach in the treatment of AIDS is to

alter genetically HIV infected lymphocytes so that they produce

proteins or nucleic acids that inhibit either the production or

escape of HIV, misdirect specific components of HIV, or are toxic to

infected cells.  A significant limitation in this approach is the

inability to engineer reliably specific functionality into an

existing protein or nucleic acid scaffold or, at a more basic level,

to design a protein or nucleic acid de novo to perform a specific

function.



o  An understanding of basic evolutionary processes by which

organisms adapt to complex environments.  The rapid evolution of the

HIV, even within a single host, is a major obstacle to vaccine and

drug development and underlies the phenomenon of multiple drug

resistance.  Knowledge about the general features which govern

adaptation and evolution is an essential step to understanding the

relationship between viral diversity and the course of infection, and

the evolution of multiple drug resistance.  These are factors that

must be considered in developing vaccines and designing drugs to make

them effective.



The purpose of this program announcement is to solicit applications

that address one or more of these key issues in ways that not only

take advantage of an investigator's existing expertise in these areas

but also encourages the investigator to recognize the implications of

his or her research to AIDS and AIDS-associated opportunistic

infections.  The expectation is that the investigator will remain

focused on the central question of AIDS during the course of the

project.



For investigators already funded by NIGMS, NIDDK, or NIAID for basic

research in these areas, a competitive supplement to provide key

links to AIDS research is encouraged.  In addition to the information

described in the application kit (PHS 398) required for a

supplemental application, the request should detail how the requested

funds will enable the investigator to enhance significantly the

applicability of the research project to AIDS and AIDS-associated

opportunistic infections.



APPLICATION PROCEDURES



Applications for regular and supplemental awards for regular research

(R01), FIRST, and MERIT grants are to be submitted on the grant

application form PHS 398 (rev. 9/91) and will be accepted at the

receipt dates for applications for AIDS-related research:  January 2,

May 1, and September 1.  Applications for regular and supplemental

awards for program project grants (P01) have receipt dates of

February 1, June 1, and October 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) 710-0267.



On the first (face) page, item 2a, of the application, the word "YES"

must be checked and the title and number of the program announcement

typed in the space provided:  "Basic Research in Support of

Treatments for AIDS, PA-94-014."  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

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Applications will be assigned to a funding component (Institute or

Center) and an Initial Review Group (IRG) on the basis of established

Public Health Service referral guidelines.  The IRGs will review

applications for scientific and technical merit in accordance with

standard NIH peer review procedures.  Following the IRG review, the

applications will receive a second-level review by the appropriate

national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered making funding

decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  The implications of the project for AIDS and an intellectual

environment that focuses on AIDS research

o  Program balance among research areas of the announcement



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



James Cassatt, Ph.D.

Biophysics and Physiological Sciences Program

National Institute of General Medical Sciences

Westwood Building, Room 907

Bethesda, MD  20892

Telephone:  (301) 594-7800

FAX:  (301) 594-7700



Carl W. Dieffenbach, Ph.D.

Division of AIDS

National Institute of Allergy and Infectious Diseases

Solar Building, Room 2C05

Bethesda, MD  20892

Telephone:  (301) 496-8199

FAX:  (301) 402-3211



Eliezar Dawidowicz, Ph.D.

Metabolism and Structural Biology Research Program

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 621

Bethesda, MD  20892

Telephone:  (301) 594-7582

FAX:  (301) 594-9011



Direct inquiries regarding fiscal matters to:



Ms. Ruth Monaghan

Grants Management Office

National Institute of General Medical Sciences

Westwood Building, Room 9A03

Bethesda, MD  20892

Telephone:  (301) 594-7813



Ms. Donna A. Huggins

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 649

Bethesda, MD  20892

Telephone:  (301) 594-7543



Ms. Carol B. Alderson

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B27

Bethesda, MD  20892

Telephone:  (301) 496-7075



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance Nos. 93.821, 93.859, 93.862, and 93.863.  Awards are

authorized by sections 301 and 405 of the Public Health Service Act,

as amended, 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 Systems Agency review.



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