RFA-GM-05-008: HIGH-ACCURACY PROTEIN STRUCTURE MODELING

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HIGH-ACCURACY PROTEIN STRUCTURE MODELING RELEASE DATE: July 8, 2004 RFA Number: RFA-GM-05-008 EXPIRATION DATE: February 15, 2005 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. Replacement R01 (RFA-GM-07-003) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.859(NIGMS) LETTER OF INTENT RECEIPT DATE: January 14, 2005 APPLICATION RECEIPT DATE: February 14, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The NIGMS invites applications for P20 Exploratory Center Grants to support the development of novel technologies that will significantly improve the accuracy of comparative modeling methods for protein structure prediction. This program is part of the NIGMS-supported Protein Structure Initiative (PSI). The purpose of this RFA is to foster rapid advances in high-accuracy protein structure modeling by promoting interdisciplinary collaborative research with the aim of producing models comparable in quality to experimentally determined structures for most proteins. RESEARCH OBJECTIVES Background With the completion of well over a hundred genome sequences including the human genome, functional characterizations of proteins encoded by the genomes have inevitably come to the front of the stage. Three- dimensional (3D) structural studies provide a unique contribution in understanding the functions of proteins, and enabling structure-based drug design. Recent technology advances in X-ray crystallography and NMR spectroscopy have dramatically reduced the time and effort required for protein structure determination, making it possible to consider a strategy of high-throughput structure determination for a large number of proteins composing functional related families, signaling pathways, and entire proteomes. The NIGMS launched the PSI program in 2000 to explore different approaches to large-scale protein structure determination (see program information at http://www.nigms.nih.gov/psi/). The long-range goal of the PSI is to make 3D structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences. The PSI program is projected to determine about 8,000 experimental structures of protein family representatives by 2010. With improved methods of comparative modeling, it may be feasible to produce a million high- resolution protein structure from the 8,000 that will be directly determined experimentally. The efficiency in experimental structure determination and the quality of the computational models will be the two main determinants of the overall success of the PSI program. The PSI research centers are making rapid progress on the experimental front. The number of structures determined by these centers has doubled every year, while the average cost per structure is continually dropping. Unlike most of the submissions to the Protein Data Bank (PDB) that are highly homologous to previously determined structures, the majority of the structures solved by the PSI centers have 30% or lower sequence identity to previous depositions in the PDB. Since these PSI structures have much lower redundancy to known structures, they will provide much broader coverage of sequence families and possible protein folds. The production phase of the PSI is scheduled to start in the summer of 2005 (see RFAs at http://grants.nih.gov/grants/guide/rfa-files/RFA-GM-05-001.html and http://grants.nih.gov/grants/guide/rfa-files/RFA-GM-05-002.html). It is anticipated that in two to three years, the number of non-redundant structures produced by these large-scale structural genomics centers and other structural biology laboratories will be over one thousand a year. The availability of these structures will enable homology modeling for several hundred thousand proteins. The value of these structural models in biological research depends critically on their quality. Development of high-accuracy computational methods that reliably generate experimental-quality structural models will be essential for capitalizing on the PSI investment, and furthermore will benefit all biomedical researchers relying on structural information of proteins for their functional investigations. Unlike the rapid advances made in experimental structure determination, progress in computational structure prediction has been incremental as illustrated at the recent CASP (Critical Assessment of Methods for Structure Prediction of Proteins, http://www.forcasp.org) competitions. Predictions that rely on closely related template proteins with known structures in general have much higher quality than ab initio methods. Reliability of these homology modeling or comparative modeling methods depends critically on the level of sequence identity between the modeling target and the template. When sequence identity is 30% or higher, backbone atoms are usually correctly modeled. The majority of the errors come from side-chain and loop placement during refinement with roughly 3-4 angstrom root mean square deviation (RMSD) compared to high-resolution crystal structures. When the sequence identity drops below 30%, misalignment happens frequently and model quality suffers dramatically. To increase the utilization and value of the computational models in biomedical research, and to reduce the need for still costly experimental structure determination, significant improvement in the reliability and accuracy of modeling techniques is needed by the research community. Recognizing the need for much improved protein structure modeling technology, the NIGMS organized a High-Accuracy Comparative Modeling Workshop soliciting community input in October, 2003. The workshop participants identified some specific areas as bottlenecks for further development of protein structural modeling. A workshop summary is published on the NIGMS website (http://www.nigms.nih.gov/psi/reports/comparative_modeling.html). The aim of this RFA is to foster scientific progress in computational protein structure prediction that will reliably produce models with accuracy close to experimentally determined X-ray crystal structures. In order to achieve this goal, novel concepts and strategies are needed to significantly improve current comparative modeling methods. Close collaborations among creative researchers with various training backgrounds and expertise are expected to provide cross fertilization for the development of new approaches. Although hurdles are still high, potential payoff and impact will be dramatic. The ultimate goal is a paradigm shift in structural biology, so that experimental structure determination for most soluble single proteins will become unnecessary, and more resources and effort can be put into characterizations of complexes and more difficult targets. Eventually, accurate structural information will be available for all the gene products. Scope of Research This RFA aims to promote interdisciplinary team research and exploratory approaches in developing novel comparative modeling technology. Cross-disciplinary collaborations with the inclusion of, for example, physicists, mathematicians, computer scientists, and statisticians who are new to the field are required. Collaborations with the PSI research centers (http://www.nigms.nih.gov/psi/centers.html) are encouraged. The technologies developed should be scalable for applications on larger data sets of various kinds of proteins, rather than on a limited number of a special kind of proteins. Applicants for this RFA should focus on one or both of the following two main goals (also see Award Criteria): 1) Comparative Modeling Goal 1: Crystal Structure Quality for Close Homologs of Known Structures The first scientific goal of this RFA is to achieve the standard of high-resolution X-ray crystal structure quality for comparative models that are based on known structures with higher homology (30% sequence identity) to the modeling targets. This is predominantly a high- accuracy refinement problem, although substantial improvement of alignment methods is also required. The aim is to acquire the ability to reliably produce computational models with highly accurate placement of both backbone and side chain atoms, and to significantly reduce the need for experimental structure determinations for close homologs of known structures. 2) Comparative Modeling Goal 2: High-Accuracy Models for Remote Homologs of Known Structures The second scientific goal is to expand the modeling coverage to more distantly related proteins that exhibit as low as 10% identity to any known structures. The quality of these models should be close to X-ray structures or high-resolution NMR structures with less than 2 angstrom RMSD for backbone and side-chain atoms. This is both an alignment problem and a refinement problem. Significant improvement of modeling methods is needed to push the modeling coverage to remote homologs of existing structures without much compromise on quality. Through this RFA, the NIGMS is committed to achieving both of these two goals (see Award Criteria). Applicants must identify which of the modeling goals (or both) the proposal is addressing. Applicants may propose intermediate goals and deliverable milestones within the funding period. Although not the main focus, some other kinds of studies can be incorporated as components of their research. These may include: establishing benchmarks and standards for quality assessment and uncertainty estimations of the models; developing methods that will accurately predict structural changes caused by small mutations; combining computational methods and high-throughput experimental methods to develop novel hybrid approaches; improving ab initio methods for loop modeling; designing robust software packages that will build models for a large number of proteins with high accuracy and little human intervention; collaborating with other scientists to promote utilization of the models in functional studies. Applicants may also propose other research, but all activities must be in support of reaching the main goals above. The NIGMS strongly encourages potential applicants to discuss their ideas with Institute program staff and to send a letter of intent prior to submission to ensure that the application will be responsive to the mission and intent of this RFA. MECHANISM OF SUPPORT This RFA will use the NIH P20 Exploratory Center Grant award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The earliest expected award date is December 2005. This RFA might be reissued for a second time with a submission deadline in early 2006 and an expected award date in late 2006. P20 Exploratory Center Grants will not be renewable, but rather are expected to lead to mature projects that can attract funding through other mechanisms. This RFA uses just-in-time concepts. FUNDS AVAILABLE The NIGMS intends to commit approximately $3 million total cost in FY2006 to fund three to four P20 Exploratory Center Grants in response to this RFA. An applicant may request a project period of up to three years and a budget of up to $750,000 total costs per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans for the Institute include funds to support this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit an application if your domestic institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government Applications from foreign institutions will not be accepted; however, researchers from foreign institutions can participate through collaboration with domestic applicants or subcontracts. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS The P20 Exploratory Center Grant mechanism is designed to support multi-investigator team pilot research. It is expected that a cohesive group with a minimum participation of three investigators should form the body of the research team. Active participation of at least one investigator from the scientific disciplines other than structural biology, such as physics, mathematics, computer science, and statistics, who brings novel ideas and strategies to the design of the center’s research plans, is required. The level of originality of the research design and the level of participation of the investigator who has not previously worked on protein structure modeling in the research projects will be important review criteria. Plans should be presented in the application to integrate the efforts of the individual investigators and make the team a cohesive research center. Investigators currently supported to work on protein structural modeling are eligible to apply; however, their contributions to the center projects must not overlap with or be simple extensions of their supported studies. The NIGMS encourages the applicants to make plans to interact and/or collaborate with the PSI research centers that will be funded in the production phase or other research centers with similar goals. Target selection for experimental structure determination in the PSI centers is an evolving process, which usually involves clustering protein sequences into families of fine granularity (30% sequence identity) or coarse granularity (psi-blast or other profile based clustering algorithms). Following sequence clustering, representatives from the sequence families are selected for experimental structure determination. Examples of collaboration may include modeling proteins that are homologs of the structures determined by the PSI centers, predicting structures prior to release of their experimental structures by the PSI centers for quality assessment of the modeling algorithms, or development of hybrid approaches by combining computational methods with high-throughput experimental data to increase modeling quality. Other forms of collaboration with the PSI centers or other large-scale experimental structure determination projects are also encouraged. Additional plans to engage the user community and to solicit feedback to improve quality and utilization of models should also be included. Funded P20 center principal investigators (PIs) are required to attend and report the progress at the annual PSI meetings of the PSI research center PIs, the PSI Advisory Committee members, and the NIH program staff. Applicants should request travel funds in their budgets for the PIs to attend this annual meeting. The NIH requires that all products generated in the centers through this program become readily available to the entire research community. Applicants should develop and propose specific plans for sharing of data, materials, protocols, and resources, taking into consideration the guidance issued by the NIH http://ott.od.nih.gov/ and http://grants.nih.gov/grants/policy/data_sharing. There is no prescribed single license for software produced in this project. However NIH does have goals for software dissemination, and reviewers will be instructed to evaluate the dissemination plan relative to these goals: 1) The software should be freely available to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutes, and government laboratories. 2) The terms of software availability should permit the commercialization of enhanced or customized versions of the software, or incorporation of the software or pieces of it into other software packages. 3) The terms of software availability should include the ability of researchers outside the center and its collaborating projects to modify the source code and to share modifications with other colleagues as well as with the center. The application should include written statements from the officials of each of the applicant institutions responsible for intellectual property issues, to the effect that the institution supports and agrees to abide by the software dissemination plans put forth in the proposal. The plans for data sharing must be approved by NIH staff prior to award. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Jerry Li, M.D., Ph.D. Cell Biology and Biophysics Division National Institute of General Medical Sciences 45 Center Drive, Room 2As.19F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0682 FAX: (301) 480-2004 Email: lij@nigms.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Chief, Office of Scientific Review National Institute of General Medical Sciences 45 Center Drive, Room 3AN.12F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 Email: sunshinh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Ms. Grace Olascoaga Grants Management National Institute of General Medical Sciences 45 Center Drive, Room 2An.32E, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5520 Email: olascoag@nigms.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 by the date listed at the beginning of this document (January 14, 2005). The letter of intent should be sent to: Jerry Li, M.D., Ph.D. Cell Biology and Biophysics Division National Institute of General Medical Sciences 45 Center Drive, Room 2As.19F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0682 FAX: (301) 480-2004 Email: lij@nigms.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Applicants should follow the general instructions for PHS 398 application form with the exception of specific instructions relevant to this RFA given below. 1. Description (Page 2) In the Description, applicants should describe concisely the goal of the research, the innovative nature of the strategy, tasks for each component of the center, and the specific target to be reached at the end of the project period. 2. Research Plan The total page limit for items a-d of this section is 20 pages. o Item a: Specific Aims The two main goals of this RFA are to increase model qualities to a level comparable to high-resolution X-ray crystal structures when known structures are available with 30% identity to the modeling targets, and to increase model quality to near experimental quality with 2 angstrom RMSD when known structures are available with 10% identity to the targets. Specific aims should be built around serving one or both of these two main goals. Since team building is an important aspect for the Exploratory Centers, it is anticipated that aim(s) in the initial phase (first half year) of the project will be focusing on establishing a cohesive environment and platform for the proposed team research. The Specific Aims may be intermediate steps to a longer-term goal, but they should be well defined and achievable in the project period. o Item b: Background and Significance The applicants are expected to elaborate on the current state of the art, technical bottlenecks, innovative nature of the proposed research, and its capabilities and potential impact on biomedical research. A compelling reason for conducting the proposed research should be the focus of this section. o Item c: Preliminary Studies/Progress Report The purpose of this RFA is to promote development of novel ideas and approaches through close collaboration among researchers with different research backgrounds. It is anticipated that applicants may not have extensive preliminary data. New ideas relevant to this RFA may not have been fully tested. Therefore, applicants should put more emphasis on elaborating the rationale, which may be based on published data from other laboratories, for the proposed studies. Preliminary data are not required, should be kept to a minimum (within two pages), and will not be a major criterion for review. Applicants should also discuss the rationale for assembling the research team, including qualifications and selection criteria for the participating investigators and collaborators. o Item d: Research Design and Methods This section should carefully explain how the specific aims will be accomplished. What is the unique contribution of each component? Why is a multi-disciplinary team required for carrying out the proposed research? How will the interdependent collaboration be effective in carrying out the research? What are the plans for collaboration with the PSI centers or other large-scale structural biology centers? If there are doubts about the outcomes for early stages of the work, what is the contingency plan? What are the milestones and clear deliverables in this grant period? What is the long-term goal and plan for this work? What are the plans for dissemination of results and software developed to the research and user communities? USING THE RFA LABEL: 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/labels.pdf. SENDING AN APPLICATION TO THE NIH: 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 all copies of the appendix material must be sent to: Helen R. Sunshine, Ph.D. Chief, Office of Scientific Review National Institute of General Medical Sciences 45 Center Drive, Room 3AN.12F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 Email: sunshinh@nigms.nih.gov APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIGMS program staff. Incomplete applications will not be reviewed. If the application is not responsive to the RFA, the application will be returned without review. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIGMS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o 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 and assigned a priority score. o Receive written critiques. o 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment SIGNIFICANCE: Does this study address the main goals of this RFA as specified in the Research Objectives section? If the aims of the application are achieved, how will comparative modeling of protein structures be advanced? What will be the benefit to other researchers and to the biomedical research field in general if the proposed studies are supported? 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? Are the proposed milestones and goals feasible and deliverable as planned? Are the data and software dissemination plans adequate and consistent with the requirements in the Special Requirements section of this RFA? 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? This criterion is especially important since this RFA aims to promote innovative technology development to substantially improve the quality of protein structural modeling. INVESTIGATOR: Are the investigators 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? What are the track records of innovation of the investigators? What is the impact of the investigator’s achievement to his/her research field? Is there an inclusion of at least one investigator in the research team who has not previously worked on protein structure modeling as his/her research focus? Is the investigator who is new to protein structural modeling contributing in a significant way to the studies proposed? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CONSIDERATIONS: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: Multi-disciplinary Team: One purpose of this RFA is to promote collaborations between investigators with different training and expertise in order to foster development of creative new ideas and strategies in protein structure prediction. Participation of theoreticians in the center who were not principally working on protein structure modeling in the past is required. Review of the applications will put emphasis on evaluating the logic and sufficiency of contributions from each component, as well as the cohesiveness of the research team. Lack of Preliminary Data: Because of the exploratory nature of the P20 mechanism, preliminary data are not required and need not be of concern to the applicants or the reviewers. Evaluation will be based on the rationale of the proposed research, the originality and potential impact, the track records of the investigators on successfully developing innovative technologies and methodologies, and the proposed milestones and timelines for the research. Preliminary data are allowed in the application, but should be kept a minimum (within two pages) and will not be used as a major evaluation criterion. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 14, 2005 Application Receipt Date: February 14, 2005 Peer Review Date: July, 2005 Council Review: September, 2005 Earliest Anticipated Start Date: December 1, 2005 AWARD CRITERIA 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 Responsiveness to this RFA will be the major consideration for programmatic priorities. Applicants should focus on one or both of the two modeling goals listed under Scope of Research in the Research Objectives section of this RFA. The NIGMS is committed to achieving both modeling goals. The staff will consider total coverage of the two goals in the program in making award decisions. In addition, there should be sufficient innovation in the proposal. The proposed studies should be highly collaborative in nature. Any application that is dominated by a single investigator working on insignificant improvement of technologies currently supported by the NIH will be considered non- responsive to this RFA. REQUIRED FEDERAL CITATIONS SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 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. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the 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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