STRUCTURAL BIOLOGY OF AIDS RELATED PROTEINS

Release Date:  September 10, 2001

RFA:  RFA-GM-02-004

National Institute of General Medical Sciences

Letter of Intent Receipt Date:  November 15, 2001
Application Receipt Date:       December 13, 2001

PURPOSE

The National Institute of General Medical Sciences (NIGMS) reannounces its 
interest in receiving applications to apply modern methods of structure 
determination and analysis of AIDS-related proteins and those involved in 
associated infections with the ultimate goal of using structure-based drug 
design for the treatment and prevention of AIDS and associated opportunistic 
infections.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010", a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Structural Biology of AIDS Related Proteins, is related to one or more of the 
priority areas.  Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic 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; however, 
subcontracts to foreign institutions are allowable with sufficient 
justification.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the program project grant (P01).  The 
requirements are the same as those published in the recent NIGMS guide 
announcement PA01-116; July 13, 2001 
(http://grants.nih.gov/grants/guide/pa-files/PA-01-116.html) 
for program project grants.  It is expected that three 
or more investigators, all pursuing independent but interrelated projects, 
will be involved.  One scientist must be designated by the applicant 
institution as the Principal Investigator and must bear the responsibility for 
the scientific and fiscal management of the program project grant.  The 
collaborating scientists should be independent investigators in accordance 
with the recent NIGMS program project program announcement cited above.  
Equipment and other core resources necessary for the accomplishment of the 
objectives of the program project grant may be requested.  Administrative 
cores will ordinarily not be funded.

This RFA is a one-time solicitation.  Future unsolicited competing 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.  The earliest 
anticipated award date is June 15, 2002.

FUNDS AVAILABLE 

NIGMS intends to commit approximately $10,000,000 in FY 2002 to fund 7 to 9 
new and/or competing continuation grants in response to this RFA. An applicant 
may request a project period of up to 5 years and a budget for total direct 
costs of up to $5,500,000 for the five-year period.  Amounts over this total 
may be requested for facilities and administrative (F&A) costs that must be 
included as direct costs as a result of subcontractual arrangements, major 
pieces of equipment, requirements for extensive organic synthesis, or other 
exceptional needs.  Such exceptions should be discussed with, and prior 
approval obtained from, the staff contact person, Dr. James Cassatt, at the 
address and telephone number given below.

Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary. Although the financial 
plans of NIGMS provide support for this program, awards pursuant to this RFA 
are contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. 

RESEARCH OBJECTIVES

Background

In 1987 the National Institute of General Medical Sciences (NIGMS) initiated a 
program to support groups interested in developing the area of structure-based 
drug design with a specific emphasis on AIDS related systems.  Since that 
time, considerable progress has been made through this program as well as 
elsewhere at NIH, both intramurally and extramurally, and in industry.  The 
structures of several proteins have been determined.  These structures include 
the human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV) 
and feline immunodeficiency virus (FIV) proteases, the HIV reverse 
transcriptase, the zinc finger domains of the HIV nucleocapsid protein, GP41, 
the GP120/CD4 complex, the catalytic domain of integrase, and others.  A 
number of HIV protease inhibitors have either been approved or are awaiting 
approval by the Food and Drug Administration. Most importantly through the use 
of combinations of anti-AIDS drugs, effective treatment regimens are 
available.  These have resulted in prolonging the lives of many people 
infected with HIV. Also encouraging is the fact that many of the methods 
developed in part by the funding provided by this program are being used more 
widely for drug development. 

Although this progress has been significant, there is still no cure for AIDS 
and the new regimens are not viable in those parts of the developing world 
where AIDS has reached epidemic proportions.  The development of resistance to 
available anti-HIV drugs continues to plague the entire field. Finally, 
despite the major advances that have been made in the speed of protein 
structure determination and in our understanding of the theoretical basis of 
ligand binding to proteins, the limiting step in the process of drug design 
remains the lack of generalizable, efficient and reproducible approaches for 
the use of macromolecular structures to design lead compounds.  Consequently, 
we are encouraging applications focused on: 

o  developing the concepts and methodologies of structure-based drug design;
o  determining the structures of new targets, both HIV and HIV host cell 
proteins important in the life cycle of the virus, and exploiting these to 
find new lead compounds;
o  understanding the mechanisms of drug resistance in AIDS;
o  understanding host-virus interactions with an emphasis on dealing with 
these interactions as molecular machines and using the methodologies developed 
for structural studies of molecular machines, including the high resolution 
structure determination of the components, electron microscopy and single 
molecule methods.

It is expected that the structures of either AIDS-related proteins or proteins 
key to the survival of organisms that commonly cause opportunistic infections 
in people infected with HIV will serve as a test bed for any new methodologies 
developed.  

The central disciplines covered by this RFA have traditionally been X-ray 
crystallography, nuclear magnetic resonance spectroscopy (NMR) and molecular 
modeling augmented by expertise in organic synthesis, molecular enzymology, 
and virology.  The current announcement encourages expansion into the area of 
cell biology and its associated methodologies, specifically structural 
methods.  In addition, there would seem to be a wider role for chemists, not 
only for the synthesis of specific targets but for the design of molecular 
probes of processes vital to the virus life cycle.  Innovative approaches 
relevant to the thrust of this RFA are especially encouraged.

SPECIAL REQUIREMENTS

Informal interaction and exchange of information among all funded program 
groups are expected.  All awardees are required to participate in an annual 
conference. Funds to attend this meeting should be included in the budget. 
Because of the need for rapid communication of data, the three-dimensional 
coordinates of structures and associated structure factors determined as part 
of this program must be available in the Protein Data Bank at the time of 
publication.  Timely publication is expected.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of  
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research", published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.


URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances. Data that are (1) first produced in a project 
that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA. 
It is important for applicants to understand the basic scope of this 
amendment. NIH has provided guidance at: 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA (PA) in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time. If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title, the name, address, and telephone number of the Principal 
Investigator, the identities of other key personnel and participating 
institutions, and the number and title of the RFA in response to which the 
application may be submitted.  Although a letter of intent is not required, is 
not binding, and does not enter into the review of a subsequent application, 
the information that it contains allows IC staff to estimate the potential 
review workload and plan the review.  The letter of intent is to be sent Dr. 
Cassatt at the address given below by the letter of intent receipt date 
listed.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 version. 
For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

Submit a signed, typewritten original of the application, including the 
Checklist, and five signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

REVIEW CONSIDERATIONS

On receipt, applications will be reviewed by CSR for completeness and by NIGMS 
for responsiveness.  Incomplete or non-responsive applications will be 
returned to the applicant.  It should not be assumed that a site visit will be 
conducted during the course of the review of any of these applications.  Those 
applications which are complete and responsive will be evaluated in accordance 
with the criteria stated below for scientific/technical merit by an 
appropriate review group convened by the Center for Scientific Review.  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 the applications under 
review, will be discussed, assigned a priority score, and receive a second 
level review by the National Advisory General Medical Sciences Council.

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1)  Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2)  Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project as a whole?  What are the advantages of the program project mechanism 
over a collection of regular research grants (R01s)?  Does the applicant 
acknowledge potential problem areas and consider alternative tactics? 

(3)  Innovation:  Does the proposed program project grant employ novel 
concepts, approaches or method?  Are the overall aims original and innovative? 
Does the project challenge existing paradigms or develop new methodologies or 
technologies?

(4)  Investigator:  Is the principal investigator appropriately trained and 
well-suited to carry out this work and provide the leadership necessary to 
ensure success of the entire program? Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers?

(5)  Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support? 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated.
o The reasonableness of the proposed budget and duration in relation to the 
proposed research.
o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

The scientific merit of each individual project will also be assessed and a 
priority score assigned.  This assessment will be based on the scientific 
merit of the individual project based on the published criteria for regular 
research grants 
(http://grants.nih.gov/grants/guide/notice-files/not97-010.html), 
taking into account the additional strength the project gains from 
interactions with other components of the proposed program project grant and 
its potential importance to the success of the total effort.  In this context, 
it may be the case that an individual project may be highly meritorious in the 
context of the entire program project, but not make sense as a stand-alone 
research grant.

Schedule

Letter of Intent Receipt Date:    November 15, 2001
Application Receipt Date:         December 13, 2001
Peer Review Date:                 March-April, 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  June 15, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

James Cassatt, Ph.D.
National Institute of General Medical Sciences
Building 45, Room 2AS.19C, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0828
FAX:  (301) 480-2004
Email:  cassattj@nigms.nih.gov

Direct inquiries regarding review issues to:

Ranga Srinivas
Center for Scientific Review
6701 Rockledge Drive
Bethesda, MD  20892
Telephone:  (301) 435-1167
FAX:  (301) 480-2241
Email:  rs300r@nih.gov

Direct inquiries regarding fiscal matters to:

Grace Tuanmu
National Institute of General Medical Sciences
Natcher Building, Rm. 2AS.55J MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
Email:  Tuanmug@nigms.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.821.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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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