and Human Services (HHS)
EXPIRED
PILOT PROJECTS FOR THE PROTEIN STRUCTURE INITIATIVE (STRUCTURAL GENOMICS) Release Date: July 24, 2000 RFA: GM-00-006 National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov/) Letter of Intent Receipt Date: November 3, 2000 Application Receipt Date: February 12, 2001 PURPOSE The National Institute of General Medical Sciences encourages applications for research centers that will serve as pilots to examine the best approach for developing subsequent integrated, large-scale research networks in structural genomics. This is part of the Institute"s Protein Structure Initiative (PSI), whose goal is the understanding of protein structural families, structural folds, and the relationship of structure and function. These research centers should include all the constituent tasks of structural genomics and should test strategies for large-scale high throughput structure determination by X-ray crystallography and/or NMR. This RFA is a reissuance of RFA GM-99-009 (http://grants.nih.gov/grants/guide/rfa-files/RFA-GM-99-009.html). 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), Pilot Projects for the Protein Structure Initiative (Structural Genomics), 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign institutions are not eligible for research center grants. However, subcontracts to foreign institutions are allowable, with sufficient justification. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) P50 research center award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 2001. FUNDS AVAILABLE The NIGMS expects to consider funding up to three research centers, each ranging in cost no greater than $3 million direct costs for the first year. Only applications found to be responsive to this announcement and of high scientific merit will be considered for funding. 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 the 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. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Following the completion of the sequence of the human genome, a crucial step in understanding living systems is the determination of the structure and function of the entire set of gene products. Data from the genome project have led to comparative protein sequence analyses and numerous efforts to develop methodologies for the identification of protein families. Utilization of these computational analyses with structural determinations by X-ray crystallography and NMR techniques to study protein structural families constitutes the new field of structural genomics and is the goal of the NIGMS Protein Structure Initiative (PSI). These studies should lead to an understanding of structure/function relationships and the ability to obtain structural models of all proteins identified by genomics. This project will require the determination of a large number (perhaps 10,000) of protein structures in a high throughput mode. Recent and anticipated technological developments in protein structural determinations make this formidable task feasible. The availability of comparative sequence analyses and methodological improvements now make such a large-scale structural project appropriate. Three workshops sponsored by NIGMS have focussed on the practicality, constituent tasks, goals, and planning of this project. There was general agreement on technical feasibility due to advances in the development of high throughput expression systems, protein purification, and sample preparation (crystallization for X-ray crystallography and isotopic labeling for NMR). All of these likely can be organized on the large scale required. Methods for the structure determination of proteins have also improved significantly in recent years. The identification of protein families and target selection proved to be the most controversial topic and was the focus of the third workshop. A summary of these meetings can be found on the NIGMS web site at: http://www.nih.gov/nigms/funding/psi.html. Following the workshops and discussions by the National Advisory General Medical Sciences Council, it was concluded that the necessary tasks for the PSI project are feasible and that the goal of this initiative is an important scientific endeavor. The resulting basic set of protein structures and structure folds will be crucial in understanding protein structure and evolution, will contribute to the solution of the protein folding problem, and will provide insights into the relationship of structure and function. Objectives and Scope The purpose of this RFA is to announce support for research centers in the new and emerging field of structural genomics. These research centers are intended to serve as pilots that will lead to subsequent large-scale research networks in structural genomics and high throughput structural determination of proteins by X-ray crystallography and NMR methods. They should contain all of the constituent tasks of structural genomics and should demonstrate the ability to accomplish the computational and experimental facets as an integrated and high throughput operation. Effective plans for management and administration of the research centers are crucial. Attention should be paid to costs and efficiency, as well as technology development. Rapid release of data into the public databases will be required, as described below. Applicants should include the following components: 1) Family Classification and Target Selection: There are several schemes of comparative protein sequence analysis for parsing genomes into protein families and for choosing protein targets for structural genomics projects. These have been discussed in the scientific literature and at several recent scientific meetings and workshops (for example, see the NIGMS Structural Genomics Targets Workshop, referenced above). Examples for targeting schemes to choose or prioritize proteins for structural determination include: many of the proteins of single organisms with a completed genome, putative proteins of unknown function, protein families of known functions or medical relevance, and clusters of orthologous groups (COGs) spanning the three domains of life and perhaps corresponding to "ancient conserved regions." Since no single scheme has emerged as a consensus choice, this decision is left to applicants. Their experience and results in choosing an approach that can ultimately be generalized are expected to be one of the outcomes of these pilot projects. The targeting scheme should be designed to test strategies for coverage of all proteins found in nature. Applicants are expected to determine their own target selection schemes and to present detailed plans and preliminary results for this stage of their structural genomics project. 2) Generation of Protein for Biophysical Analyses: There is now considerable experience in the generation of expression systems to produce large quantities of most proteins in a form suitable for biophysical studies. Applicants for the research centers should present evidence of their capability to generate protein expression systems, to overexpress proteins, and to purify protein samples. Emphasis should be on high throughput, efficiency, and cost savings. 3) Sample Preparation for Structural Studies: This crucial experimental task has seen significant progress recently. There has been greater understanding of the basic mechanisms of crystallizations by various physical approaches. These advances have significantly improved the ability of structural biologists to crystallize proteins, especially for soluble globular proteins. NMR studies will require isotopic labeling of protein samples. The applicant"s experience and plans for the preparation of samples for structure determinations in a high throughput mode should also be presented. Crystallization of membrane proteins and a number of other classes of proteins are still very difficult and not yet amenable to high throughput operations, but innovative projects in this area as part of a larger effort are encouraged. 4) Structure Determination: With many major technical advances in recent years, X-ray crystallography for high-resolution structure determination has become straightforward for many protein samples. The major breakthrough has been the almost universal use of synchrotron beamlines, which produce high fluxes and variable wavelengths. In addition, major improvements have come from new detectors, cryocrystallographic techniques, multiple-wavelength anomalous diffraction techniques, and advanced computational systems for rapid data collection, processing, and model building. New NMR methods and higher field instruments have increased the size of proteins that can be solved by this technique. The structure determination component should be the nucleus of a structural genomics research center and applicants should have considerable expertise and resources in either or both of these techniques. The research centers should have plans for structural determinations in a high throughput mode, with emphasis on efficiency, cost reductions, and extensions to large-scale operation. The research centers are expected to demonstrate their access to state-of-the-art synchrotron and/or NMR facilities. The NIGMS is currently planning the development of additional beamlines at several synchrotron facilities, and will likely be able to make additional beamtime available to general users and research centers funded by this RFA within the next few years. However, the structural genomics research centers are expected to demonstrate their own plans for data collection and structure determinations. 5) Analyses and Dissemination of Results: With several disparate components that are interdependent, management and administration are crucial. In addition to the usual administrative details, the leadership of the research centers must have plans for directing the research, e.g., making decisions about which proteins to study first, determining when to pursue a structure and when to discontinue, coordination between different groups, etc. Since the goal of this initiative is to add to the body of knowledge of protein structure and to enable the NIGMS and scientific community to plan and prepare for large-scale operations in structural genomics, release and dissemination of results are crucial. In addition to the structure factors and coordinates, this includes information on strategies for target selections, status of research on these proteins, technological and methodology findings, high throughput approaches, efficiency, and cost analyses. The pilot research centers will be required to have plans for timely deposition of coordinates and related data into the public database and for handling intellectual property issues. They should also address their plans for analyses of results relative to understanding protein structure and the field of structural genomics. The NIGMS plans to hold annual meetings at the NIH for grantees in structural genomics to discuss their progress and results. Summary The purpose of this RFA is to call for applications supporting research centers in structural genomics. These research centers are intended to provide information to the NIH and the scientific community that will lead to subsequent development of large-scale research networks in structural genomics. Both computational and experimental aspects are essential, as well as a comprehensive and integrated research plan. Emphasis should be placed on protein structural determinations in a high throughput mode. There are two related program announcements: 1) PA-99-116. A program for R01 and P01 grants to support research on the development of methodology and technology underpinning the emerging field of structural genomics. Projects related to high throughput structure determination by X-ray crystallography and NMR, as well as those addressing other constituent tasks of structural genomics, are relevant. 2) PA-99-117. A similar program to the above for structural genomics methodology and technology development for Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) applications. POST-AWARD MANAGEMENT During the course of the grant period, both computational and experimental technologies will improve, and the rate of progress and focus of work supported by the grant may change. It is expected that the Principal Investigator will make any necessary adjustment in scientific direction to accommodate the expected scale-up and changing environment, keeping the NIGMS staff informed if significant changes are made. In order to ensure that the project remains focused on appropriate goals, incorporates new technological advances and makes sufficient progress, scientific and programmatic visits to the grantee will be conducted at a frequency to be negotiated with the awardee. In addition, benchmarks for progress may be changed annually. The NIGMS may include outside consultants in the annual progress review and reduce or withhold funds for failure to meet milestones agreed upon by grantees and NIH staff. A report by the NIGMS program director on each research center"s progress and any recommendations to modify funding will be made annually to the National Advisory General Medical Sciences Council. SPECIAL REQUIREMENTS The NIGMS has adopted several polices that are applicable to these structural genomics research centers. Applicants must present plans to adhere to the policies, where appropriate. Research Training. In most cases, the research projects envisioned at this stage of the PSI will involve extensive data collection with limited hypothesis-driven aspects. Therefore they may not be appropriate as research training projects. Applicants planning to employ graduate students and/or postdoctoral research assistants on their project should address this issue. Intellectual property. The results of the structural genomics projects should be freely available for use by the entire research community and, therefore, must be released into the public domain. Applicants should present plans related to intellectual property rights. The NIGMS will monitor its grantees" activities with respect to patenting the structural results and technology developments. Data Release and Sharing of Results and Materials. Structural results, including protein coordinates and structure factors should be deposited promptly into the Protein Data Bank (PDB). Guidelines developed by NIH do not permit holds on deposited coordinates (http://grants.nih.gov/grants/guide/notice-files/not99-010.html). In addition, dissemination of results of the structural genomics research centers is crucial and applicants should plan on sharing findings and the experiences at the annual meetings for structural genomics grantees and in other appropriate forums. This includes information on strategies for target selections, status of research on these proteins, technological and methodology findings, high throughput approaches, efficiency, and cost analyses. Grantees will be required to develop and maintain a public website showing the information listed above, as well as providing it in their annual progress report. The NIGMS is supporting the development of a database (contact Dr. Norvell at NIGMS for updated information) to facilitate this sharing of information and the coordination of the research projects undertaken by the research centers. In some cases, the proteins and samples generated by these research centers will need to be pursued by detailed functional studies by scientists both within and outside the research centers and beyond the scope of these awards. Thus, the research centers should have plans both for timely deposition of coordinates and related data and for sharing results and materials. Management Plan. The management of a structural genomics research center requires a significant commitment by the Principal Investigator. Accordingly, he or she is expected to devote a substantial effort to the project. The applicant must propose a management plan that takes into account the changes that will occur over the 5-year term of the award. External Scientific Advisory Committee. Each research center should have an external advisory committee of research scientists not involved in the consortium to provide independent assessment and advice to the Principal Investigator and staff. This committee should be appointed by the Principal Investigator and meet at least twice each year. In order to maximize the pool of possible reviewers, the potential members of the advisory committee should not be contacted or selected until after an award has been made. Annual Meeting. Grantees in the PSI program will be expected to attend an annual meeting at the NIH to discuss their progress and results. 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 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 of 1993 (Section 492B 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 was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and is available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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. 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. LETTER OF INTENT Prospective applicants are asked to submit, by November 3, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, abstract, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application will be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows Institute staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: John C. Norvell, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences 45 Center Drive, Room 2AS.13B Bethesda, MD 20892-6200 Telephone: (301) 594-0533 FAX: (301) 480-2004 Email: [email protected] APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted only at the deadline of February 12, 2001. Application kits are available at most institutional offices of sponsored research, on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html, and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, email: [email protected]. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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, ("Protein Structure Initiative," GM-00-006) must be typed on the RFA label and on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Potential applicants are strongly urged to contact the program staff listed under INQUIRIES for guidance in the preparation of the application. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. Special application requirements The research center should be an integrated, coordinated project, with various interdependent subprojects that comprise structural genomics as described above. The subprojects should be organized to be consistent with the five components of structural genomics that were listed above in the section "Research Objectives." They must be fully described and justified. Collaborations and consortia are encouraged. In such collaborations, the respective contributions should be well integrated into the design of the application. The application should have a face page, abstract, project summary, plans for administrative management, plans for project management with annual milestones and evaluations, subproject descriptions, consolidated budget, subproject budgets, key personnel listing, biographical sketches, investigators" other support, institutional support, resources and facilities, letters of collaboration, plans for sharing results and materials, plans for handling intellectual property issues, etc. An overview section should be prepared that includes an overall description which defines the scope and objectives. The budget should be no greater than $3 million direct costs (facilities and administrative (F&A) costs on subprojects are not included in this cap) for the first year, with annual cost-of-living increases in subsequent years. It should be fully justified and should include funds for attending the annual meeting. The page limit for the research plan (including specific aims, background and significance, preliminary studies, and research design and methods) is increased to 60 pages total. Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional copies of the application and any appendix material must be sent to: Helen R. Sunshine, Ph.D., Chief Office of Scientific Review National Institute of General Medical Sciences Building 45, Room Number 1As.13 National Institutes of Health Bethesda, MD 20892 Applications must be received by February 12, 2001. 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 Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness to the RFA by the NIGMS program staff. Incomplete and/or nonresponsive applications will be returned to the applicant without further consideration. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIGMS. Site visits or applicant interviews may or may not be performed as part of the initial review. Applicants should not assume they will occur and therefore must present a complete and well-justified written proposal. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory General Medical Sciences Council. Review Criteria 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. 1. Significance: Will this research project make an important contribution to the field of structural genomics? 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? What is the likelihood that the research center will be able to evolve into a successful large-scale high throughput structure determination research network? 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? Is the management and administrative framework adequate? Are the milestones and plans for evaluations appropriate? 3. Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? How exportable are these strategies and technologies? Is there a plan for incorporating new technologies at reasonable costs? 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? Does the Principal Investigator have the appropriate management and administrative skills? 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed research centers take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there adequate 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 Plans for protein family classification and target selection, including plans for testing this strategy and its applicability to subsequent large- scale research networks. o Plans and previously demonstrated success in increasing throughput and decreasing costs. o Plans for handling intellectual property issues, for sharing results and materials generated by this research, and for prompt placement of data in the public domain, including deposition of coordinates in the Protein Data Bank. o The reasonableness of the proposed budget in relation to the proposed research, and 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. Schedule Letter of Intent Receipt Date: November 3, 2000 Application Receipt Date: February 12, 2001 Peer Review Date: June 2001 Council Review: September/October 2001 Earliest Anticipated Start Date: September 2001 AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the NIGMS. Awards will be made in September 2001. The following will be considered in making funding decisions: o quality of the proposed project as determined by peer review, o program priority of research in this area and other areas of Institute interest, o plans for rapid dissemination of the results and information on technological developments, including rapid deposition and release of all protein coordinates and structure factors into the PDB, i.e., holds on release are not permitted, o overall contribution of the project to knowledge and experience required to meet the long range goals of the structural genomics project, and o availability of funds. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: John C. Norvell, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences 45 Center Drive, Room 2AS.13B Bethesda, MD 20892-6200 Telephone: (301) 594-0533 FAX: (301) 480-2004 Email: [email protected] Direct inquiries regarding fiscal matters to: Ms. Grace Tuanmu Grants Management Office National Institute of General Medical Sciences 45 Center Drive, Room 2AS.55J Bethesda, MD 20892-6200 Telephone: (301) 594-5520 FAX: (301) 480-2554 Email: [email protected] 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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