Full Text PA-97-090 THREE-DIMENSIONAL STRUCTURES OF IMMUNOLOGICAL PROTEINS NIH GUIDE, Volume 26, Number 26, August 8, 1997 PA NUMBER: PA-97-090 P.T. Keywords: National Institute of Allergy and Infectious Diseases PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for research on the three-dimensional structural properties of proteins involved in initiating and regulating immune responses in human and animal systems. The structural elucidation of protein complexes and development of structural analogs that enhance, inhibit or change the function of native proteins for therapeutic applications are also of interest. Increased knowledge of immunological proteins obtained from such structural studies is important for understanding regulation of the immune system and for the development of effective immunotherapeutic agents. 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 Program Announcement (PA), "THREE-DIMENSIONAL STRUCTURES OF IMMUNOLOGICAL PROTEINS", is related to the priority area of Immunization and Infectious Diseases. 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 Applications may be submitted by 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. Domestic and foreign institutions are eligible to apply for R01 grants. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant(R01)and FIRST (R29) applications may be submitted in response to this program announcement. Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support. Applicants for the FIRST award must comply with the NIH Guidelines for FIRST awards and the Just-in-Time procedures announced in the NIH Guide, Vol. 25, No. 10, March 29, 1996. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background Detailed structural analyses of antibody:antigen and peptide:MHC complexes and, more recently, the T cell antigen receptor, have provided information at the three-dimensional level that is essential for understanding the rules of ligand:receptor associations and specific sites of protein:protein interactions for these fundamental components of the immune system. Many additional immunologically relevant proteins have not yet been defined at the three-dimensional level, and such information would contribute greatly to basic understanding of immune reactions and to the rational design and effective utilization of therapeutic agents that enhance or inhibit immune responses. Although genetic mutational or biochemical studies can provide useful information, biophysical approaches, such as X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, provide direct and more definitive descriptions of important structural domains. Detailed knowledge of molecular topography and contact sites that are important for functional activation can, therefore, form the basis for understanding fundamental concepts in immunoregulation and identify new targets for immunotherapy. Three-dimensional structural studies may confirm protein structures postulated from less direct experimental approaches, or may provide surprising and highly instructive data that are relevant for protein function. In addition to work on antibodies, MHC and the T cell antigen receptor, some examples of the importance of X-ray crystallographic or NMR data include the development of HIV-protease inhibitors and understanding the role of invariant chain in MHC class II antigen presentation. In addition, structural analysis of protein dimerization mediated by the immunosuppressive drug, rapamycin, has spurred efforts to design structure-based strategies for regulating intracellular signal transduction pathways and transcription factor activation. Knowledge of three-dimensional structures may also engender novel hypotheses that are amenable to experimental testing to provide a more comprehensive understanding of immune mechanisms. Furthermore, the biophysical data obtained from three-dimensional studies may form the basis for construction of peptidomimetic analogues of immunologically relevant proteins to provide more stable and effective therapeutic drugs. Research Objectives and Scope The purpose of this PA is to support research on three-dimensional structures of immunologically relevant proteins and protein complexes. It is NOT intended to support indirect structure:function studies that rely solely on genetic or biochemical techniques. Research areas of interest include, but are not limited to, structural studies on: o soluble immune mediators, such as antibodies, cytokines and chemokines, and their receptors; o leukocyte membrane adhesion or signaling receptors and their ligands; o signal transduction molecules; o transcription factors involved in leukocyte activation or downregulation; o structural analogues of immunological proteins that enhance, inhibit, or introduce a novel function for therapeutic application; and o novel technologies to facilitate three-dimensional structural analysis. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority group 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 are provided 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 1993 (Section 4928 of Public Law 103-43). 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or 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 for PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title, "THREE-DIMENSIONAL STRUCTURES OF IMMUNOLOGICAL PROTEINS" must be typed in section 2. The completed, signed original and five legible, single-sided copies of the application must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) FIRST (R29) award 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. Applicants from institutions that have a General Clinical Research Centers (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. Incomplete applications will be returned to the applicant without further consideration. 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. 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 appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 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? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; 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 favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Helen Quill, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A22 Bethesda, MD 20892-7640 Telephone: (301) 496-7551 Fax: (301) 402-2571 EMAIL: hq1t@nih.gov Direct inquiries regarding fiscal matters to: Lesia Norwood Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B27 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Fax: (301) 480-3780 Email: ln5t@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are No. 93.855 - Immunology, Allergy, and Transplantation Research and No. 93.366 - Aging Research. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems 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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