Full Text PA-95-087 METABOLIC ENGINEERING NIH GUIDE, Volume 24, Number 32, September 1, 1995 PA NUMBER: PA-95-087 P.T. 34 Keywords: Metabolism Genetics Biology, Cellular Enzymology 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 research that will expand the conceptual and experimental basis of metabolic engineering. Basic research that contributes to a quantitative understanding of the integration and control of genetic, catalytic, and transport processes that comprise metabolism is encouraged, as is research to create techniques that facilitate the exploitation of metabolic processes for biomedical uses. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, eligible agencies of the Federal government. Applications from minority individuals and women are particularly encouraged. Foreign institutions are not eligible to receive First Independent Research Support and Transition (FIRST) awards (R29) or program project grants (P01). MECHANISM OF SUPPORT Support of this research will be through the individual research project grant (R01), program project grant (P01), FIRST Award (R29). Potential applicants for program project grants are strongly urged to contact the program staff listed under INQUIRIES for guidance concerning both the organization and scope of the proposed work and the preparation of the application itself. RESEARCH OBJECTIVES The study of intermediary and secondary metabolism at one time was the centerpiece of biochemistry and cellular physiology. This endeavor provided one of the first examples that cellular processes could be understood in molecular terms; it also brought into sharp relief the importance of enzymes as critical mediators of cellular activities. Despite the successes of decades of investigations of cellular metabolism, there still appears to be a vast amount to be learned about metabolism. While it is true that the enzymological sequences and intermediates of many metabolic pathways in a small number of well-studied organisms are known with some confidence, little is known in quantitative terms of the controls and integration of these pathways. Hence, it is difficult to predict rigorously the responses of metabolism to environmental changes and shifts in developmental programs. Investigations of these facets of intermediary and secondary metabolism are hampered by an inability to examine intracellular metabolite concentrations and enzyme activities in vivo, and by a lack of adequate analytical models to organize and describe the data. It is also clear that there is limited knowledge of the range of extant metabolic potential. There are vast numbers of organisms that have never been examined metabolically; some of these, such as the archaebacteria, various anaerobic bacteria, and marine microbes may utilize metabolic systems that are biochemically fascinating and potentially useful. An emerging approach to the understanding and exploitation of metabolic processes is metabolic (or pathway) engineering. As the name implies, metabolic engineering is the targeted and purposeful manipulation of the pathways of an organism. Metabolic engineering typically involves the alteration of cellular activities by the manipulation of the enzymatic, transport, and regulatory functions of the cell through the use of recombinant DNA and other genetic techniques. Much of this effort has focussed on microbial organisms, but important work is being done in plants, and cultured cells from both plants and animals. The prospects for successful metabolic engineering can be seen in two areas. On the one hand, it can be used to create a microbial or plant-based production route for useful quantities of "small" molecules, such as amino acids and other nutritionally important molecules, antineoplastics, various antibiotics (or their derivatives) and other valuable secondary metabolites. On the other hand, metabolic engineering can also provide a route to targeted metabolic changes useful in the exploration of the control architecture that integrates the genetic and catalytic processes in both normal and aberrant cells. While this latter approach is widely used already in contemporary cell biology, the systems-oriented, quantitative tools of metabolic engineering could provide access to an understanding of metabolic pathways that is significantly more amenable to mathematical analysis and modelling. The purpose of this program announcement is to promote investigations into the nature of metabolism, its control and its biomedically useful exploitation. Through this program announcement the National Institute of General Medical Sciences (NIGMS) is encouraging the submission of applications for grants to support research into such topics as the following: o the control mechanisms and the determinants of flux for pathways where these factors are not well understood; o the development and application of analytical instrumentation and techniques to study quantitatively the in vivo behavior of metabolic enzymes and regulatory molecules; o the identification of additional genetic tools, e.g., selective markers, reporter genes, vectors, and regulatory molecules for the introduction of targeted synthetic or regulatory capacity into host cells; o the creation of a broader range of host cells for the introduction of heterologous genes; o the enhancement of techniques for maintaining the viability and genetic stability of engineered cells; o databases and computational tools for pathway analysis that would facilitate quantitative modelling of metabolism; o the development of an improved understanding of the determinants of small molecule transport; o the exploration of systems showing potentially novel metabolic capacities, such as plants and diverse microbes. This listing is not meant to be all-inclusive. There are, no doubt, many areas of research, not specified above, that could contribute to both an expanded understanding of metabolic processes and a substantial broadening of their utilization for biomedical ends. It is expected that some of the research projects proposed in these areas would rely on collaboration between investigators from different disciplines -- biochemistry and chemical engineering, for example. Such collaborations, where two or more approaches can enhance the likelihood of success, would be welcome, but are not required. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) 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, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892, telephone (301) 435-0714. The title and number of this program announcement must be typed in Section 2 on the face page of the application (i.e., "Metabolic Engineering," PA-95-). For investigators applying for support through the FIRST Award mechanism (R29), three letters of reference must be submitted with the application attached to the face page. FIRST (R29) award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. An applicant submitting a revised application in response to this program announcement must again submit reference letters. The completed original application and five legible copies must be sent or delivered to: OFFICE OF GRANTS INFORMATION DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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 adequacy of plans to include both sexes and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. 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. 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: Warren Jones, 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) 594-5938 FAX: (301) 480-2802 Email: JONESW@gm1.nigms.nih.gov James Anderson, Ph.D. Division of Genetics and Developmental Biology National Institute of General Medical Sciences 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0943 FAX: (301) 480-2228 Email: ANDERSOJ@gm1.nigms.nih.gov Catherine McKeon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5AN-18B 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: McKeonC@ep.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 Huggins Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-49K 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8848 FAX: (301) 480-3504 Email: HugginsD@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Numbers 93.821, 93.847, 93.859, and 93.862. 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 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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