Full Text PA-95-035 STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS NIH GUIDE, Volume 24, Number 7, February 24, 1995 PA NUMBER: PA-95-035 P.T. 34 Keywords: 0760044 Proteins and Macromolecules Membrane Structure/Function Ultrastructure National Institute of General Medical Sciences National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The purpose of this program announcement (PA) is to encourage basic research on the structures of membrane proteins at (or near) atomic resolution. Considerable research is on-going in the area of membrane protein structure and function, particularly with respect to sequences, topology, and the effects of mutations; however, much of this work is somewhat speculative in that the interpretations depend upon the very limited number of structures that have actually been solved by direct biophysical measurements. An increase in the number of known membrane protein structures will contribute to an enhanced understanding of many basic phenomena underlying cellular function. 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 and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards and program project (P01) grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Support of this program will be through the individual research project grant (R01), program project grant (P01), and FIRST award (R29). Potential applicants are strongly urged 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 R01, P01, or MERIT (R37) grants to study membrane associated processes and who are not currently supported for work on high resolution structural studies of the relevant membrane associated proteins may wish to consider applying for competing supplemental awards (S01). RESEARCH OBJECTIVES Membrane proteins play a crucial role in many cellular and physiological processes. They are essential mediators of material and information transfer between cells and their environment, between compartments within cells, and between compartments comprising the organ systems. Functionally normal membrane proteins are vital to health and specific defects are associated with many known disease states. Membrane proteins are the targets of a large number of pharmacologically and toxicologically active substances and are responsible, in part, for their uptake, metabolism, and clearance. Despite the importance of membrane associated proteins, the knowledge of their high resolution structures and mechanisms of action has lagged far behind the knowledge of these properties of proteins in general. This has resulted from the difficulty of obtaining x-ray diffraction quality crystals for the membrane-embedded domains of these proteins and the difficulty of applying well developed solution NMR methods to the study of most membrane proteins. These difficulties have led to a reluctance of many investigators to pursue high resolution structural studies. However, in the recent past, advances in methods for crystallization and analysis of proteins by x-ray and electron diffraction methods, and improvements in NMR methods, particularly solid-state NMR, have led to new opportunities. The objective of this program announcement is two-fold: 1) To encourage investigators with interests in membrane associated systems to pursue high resolution structural studies making use of these recently developed technologies; and 2) To encourage additional research to further develop methods for studying the structure of membrane proteins at atomic resolution. Areas identified as needing specific attention include: o Improved methods for over-expression of native and modified membrane proteins, o Improved methods for isolation, purification, and stabilization of membrane proteins, including the development of new detergents and non-detergent solubilization agents, o Basic research on the physical chemistry of membrane protein crystallization and the development of new methods for crystallization and crystal manipulation that could facilitate data collection, o Further development of methods for electron diffraction, particularly for the production of suitable 2D-crystals, o Further development of NMR methods for examining proteins in their native lipid environments. The techniques of x-ray or electron diffraction and of NMR spectroscopy have been emphasized in this announcement, since it is felt that they show the most promise for producing complete high resolution information for the largest number of proteins. However, funds are also available for research using other methods that can provide atomic resolution information in selected cases. Methods that can elucidate the organization of lipid and detergent molecules within protein crystalline arrays (e.g., neutron diffraction) are also of interest. It is expected that many of the projects will be collaborative efforts between biochemists and molecular biologists with expertise in the isolation and characterization of membrane-bound proteins and biophysicists with expertise in x-ray crystallography, NMR, and other structural methods. A major aim of this program announcement is to stimulate such collaborations. Membrane protein systems of particular interest to the National Institute of General Medical Sciences (NIGMS) include: energy transducing membranes of mitochondria, chloroplasts, and bacterial cell membranes involved in electron transport and ATP synthesis; transporters of ions, substrates, and macromolecules between intracellular compartments and between the cell and its environment; enzymes in the synthesis and metabolism of lipids, membrane-associated and secreted proteins, and glycoconjugates; cytoskeletal proteins, including those required for intracellular vesicle transport, cell motility, and cell division; regulators of cell-cell communication, differentiation, and growth; receptors relevant to cell cycle regulation, mechanisms of anesthetic action, and trauma and burn physiology; transporters and enzymes responsible for the uptake, metabolism, and clearance of drugs, or in other ways affecting the bioavailability, pharmacokinetics, or action of drugs; targets of drug action and toxicity, including targets of naturally occurring toxins and venoms; enzymes involved in the biosynthesis of natural products. Membrane protein systems of particular interest to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) should have specific relevance to one of the following programmatic areas: cystic fibrosis; carbohydrate metabolism and its hormonal control; diabetes mellitus; hormone receptors and signal transduction; endocrine disorders; normal and abnormal processes of lipid, protein, amino acid, urea, pyrimidine, metal ion and steroid metabolism; genetic metabolic disorders; diseases of peroxisomal metabolism; diseases of transport; diseases of amino acid metabolism. Proteins should be of mammalian origin. Studies on proteins of prokaryotic or lower eukaryotic origin should be proposed as models for mammalian systems. An example of this is the ABC transporter superfamily or traffic ATPases in bacteria and yeast that serve as models for the cystic fibrosis transmembrane regulator (CFTR). The above listings are not meant to be exclusive. Structural information obtained for any membrane protein will contribute to understanding the general principles that underlie all membrane protein structure and function. Research on the non-membrane embedded proteins associated with many of the cellular functions listed above is also supported by NIGMS and NIDDK; however, this program announcement is intended to emphasize the need for additional research on structural aspects of the membrane-embedded proteins involved in these processes. 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. 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. The title and number of the program announcement must be typed in Section 2a on the face page of the application (i.e., "Structural Biology of Membrane Proteins," PA-95-035. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) 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 6701 Rockledge Drive - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express mail) 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 (or, for P01s, by review group of the NIGMS or NIDDK), in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. 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 for R01 applications submitted by foreign organizations: availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing United States resources. The initial review group will also examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that Institute or Center. The following will be considered in making funding decisions: o quality of the proposed project as determined by peer review; o availability of funds; o program priority of research in the area of the program announcement and other areas of Institute or Center interest. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Peter C. Preusch, Ph.D. Division of Pharmacology, Physiology, and Biological Chemistry National Institute of General Medical Sciences 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-1832 FAX: (301) 480-2802 Email: PREUSCHP@gm1.nigms.nih.gov James C. Cassatt, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0828 FAX: (301) 480-2004 Email: CASSATTJ@gm1.nigms.nih.gov Eliezar Dawidowicz, Ph.D. Metabolism and Structural Biology Research Program National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6200 Telephone: (301) 594-8811 FAX: (301) 480-3503 Email: LENNYD@dvsgate.niddk.nih.gov Direct inquiries regarding fiscal matters to: Ms. Ruth Monaghan Grants Management Office National Institute of General Medical Sciences 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5135 FAX: (301) 594-2554 Email: MONAGHAR@gm1.nigms.nih.gov Ms. Donna A. Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8843 FAX: (301) 480-3504 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.3821, 93.847, and 93.859. 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 285c-8 and 285k) 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 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. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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