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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