SPECIALIZED CENTERS FOR THE PROTEIN STRUCTURE INITIATIVE RELEASE DATE: April 1, 2004 RFA Number: RFA-GM-05-002 EXPIRATION DATE: October 16, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) National Center for Research Resources (NCRR) (http://www.ncrr.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.859, 93.389 LETTER OF INTENT RECEIPT DATE: September 10, 2004 APPLICATION RECEIPT DATE: October 15, 2004 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 National Institute of General Medical Sciences (NIGMS) and the National Center for Research Resources (NCRR) encourage applications for cooperative agreements to support specialized structural genomics research centers for methodology and technology development and new ideas and approaches for protein production and structure determination for classes of challenging proteins. These specialized centers will form one component of the Protein Structure Initiative (PSI) Research Network, the integrated second, or production, phase of the PSI (PSI- 2). They will focus on challenging proteins that are not currently amenable to high throughput and therefore represent major bottlenecks of the structural genomics pipeline. These classes of proteins include, but are not limited to, membrane proteins, small protein complexes, and proteins from human and other higher eukaryotes. The specialized centers will also be required to produce and determine the structure of significant numbers of these proteins, especially in the later years of the project. RESEARCH OBJECTIVES A. Background With the completion of the sequencing of the genomes of human and other organisms, attention has focused on the functional characterization of large sets of proteins. The availability of sequence data, computational analyses of protein sequence families, technological developments in x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and the growing impact of structural biology on biomedical research has led to an international effort to determine protein structures on a large scale and to the emerging field of structural genomics. The NIGMS played a major role in the early planning for this field and in 1999 organized a national program, the Protein Structure Initiative (PSI). The long-range goal of the PSI is to make the three-dimensional atomic level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences. The PSI plans to accomplish this goal by the creation and distribution of a large collection of protein structures. Structural studies by X-ray crystallography and NMR in a high throughput mode of operation will achieve a systematic sampling of major protein families. These experimentally determined structures will be used as templates for computational modeling of related protein homologs to produce structural coverage of a majority of sequenced genes. As it grows, the PSI collection of structures is expected to have a significant impact on biological and medical research, in a way similar to the human genome project. These structures will help researchers discover the functions of proteins, design better experiments, and study key biomedical problems such as protein folding, structure prediction, and the organization of protein families and folds. In addition, the results of these studies will be useful for faster identification of promising new structure-based medicines, better therapeutics for treating both genetic and infectious diseases, and development of technology and methodology for protein production and crystallography. For more details about the PSI's goals, organization, and benefits, see the PSI mission statement at: http://www.nigms.nih.gov/psi/mission.html. Additional information about the PSI can be found under the links listed below. Prior to initiating the PSI, the NIGMS organized three workshops composed of experts from the scientific community to examine feasibility, constituent tasks, goals, planning, and target selection for this project. There was general agreement on technical feasibility due to advances in the development of high-throughput expression systems, protein purification, sample preparation, and structure determination by X-ray crystallography and NMR. It was agreed that all tasks could be organized on the large scale required. A summary of these meetings can be found on the NIGMS web site at: http://www.nigms.nih.gov/psi/. Following these workshops and discussions by the National Advisory General Medical Sciences Council (NIGMS Council), the PSI was initiated. The pilot phase of the PSI began in 2000 with a 5-year program for the development of research centers. The principal goal of the pilot phase is the development of a structural genomics pipeline for the determination of unique protein structures in a high-throughput operation. This program was designed to test all facets and strategies for the subsequent production phase of the PSI. Protein targets are chosen as representatives of sequence families and thus provide broad structural coverage of sequenced gene products. Most of the nine pilot centers use the 30% sequence identity rule (less than 30% of the sequence is identical to the sequence of a known structure) and/or profile methods to identify targets for unique protein structures. Each pilot center also includes other criteria relevant to feasibility and its own scientific mission: biological function, medical relevance, etc. Over 70% of the structures produced by the PSI pilot centers are unique by the 30% sequence identity rule. Duplication of effort is avoided by the public listing of all protein targets (See Special requirement B.1). Major investments in technology and methodology development at the nine PSI research centers are making each step of experimental structure determination more efficient, less expensive, and more likely to succeed. More information on the nine PSI pilot centers and the technological developments can be found at the PSI website: http://www.nigms.nih.gov/psi/. In addition to the PSI pilot research center program, the Institute has supported the development of methodology and technology underpinning the structural genomics through two research programs for individual investigators, program projects, and small business grants (PA-99-116 and PA-99-117, http://grants.nih.gov/grants/guide/pa-files/PA-99-116.html and http://grants.nih.gov/grants/guide/pa-files/PA-99-117.html ). The NIGMS PSI program has also sponsored and/or organized numerous workshops for the pilot centers to address technical bottlenecks to high-throughput operation. These workshops covered the following: structural genomics bottlenecks, x-ray diffraction, NMR, protein production, data deposition, protein production and crystallization, data management, homology modeling, and target selection. Researchers in the pilot projects have used a diversity of approaches to overcome these problems, and progress has been reported in the workshops, scientific meetings, and various publications. Reports of these workshops are available at the PSI website at: http://www.nigms.nih.gov/psi/meetings.html. A central mission of NCRR is to support the creation and dissemination of sophisticated technologies and methods critical to a broad range of biomedical research. These technologies serve as a catalyst for discovery within the broader community. NCRR has historically invested substantial resources in the development of broadly accessible, cutting-edge technology for X-ray crystallography and, more generally, structural biology. Participation in this RFA leverages and extends these previous investments. B. Programmatic Summary Analyses of the results of the pilot research centers by the NIGMS staff, PSI Advisory Committee (See Special requirement A.8), and the NIGMS Council, have led to the following summary: 1. Structural genomics pipelines can be constructed and scaled-up. This process takes considerable investment in robotic instruments, laboratory and data management systems, staff training, etc. Scaling- up takes time and care but can be accomplished. 2. High-throughput operation works for many proteins and has led to many successful determinations of protein structures. The development and incorporation of robotic instruments, standard protocols, and laboratory/data management systems have made notable impact on cost, efficiency, success, and time in the passage from DNA sequence to structure. Thus far, most of the proteins that have been solved are the low-hanging fruit - easy to express and purify. 3. The structural genomics approach of choosing multiple targets is successful. Although the automated approaches are effective, the chance of successfully determining a structure for a given target is still not high. However, with multiple targets available for most protein families, the likelihood of obtaining the structure of one family representative is significantly increased. 4. Bottlenecks remain for some proteins, such as membrane proteins, proteins from human and other higher eukaryotes, and small protein complexes. These challenging proteins are significantly more difficult to produce and crystallize and they are the subject of this RFA. 5. A coordinated, 5-year target selection policy must be developed. The pilot phase approach has worked well, with few duplicate structures produced and most of the structures being unique family representatives at the time of deposition. Additional coordination on target selection is necessary in PSI-2, with the higher level of protein structure output that is expected. 6. Homology modeling methods need improvement. Steady improvement has been noted in the methods for comparative homology modeling. However, major improvement is needed to improve the accuracy of the models and decrease the number of experimental structures that need to be determined. 7. The impact of the PSI to the broad scientific community should be increased. Benefits from the PSI structures and technologies are growing, but more activities are needed to utilize these results fully. C. Objectives The purpose of this RFA is to announce support for specialized centers for methodology and technology development for classes of challenging proteins. These research centers will be the second component of the PSI Research Network in structural genomics. PSI Research Network: In the production phase, the PSI will consist of an interacting network with four components. o In the first component, large-scale research centers will perform every step of the structural genomics process starting with DNA sequences and leading to the determination of unique protein structures in a high throughput operation. This large collection of unique structures is expected to meet the PSI goals for structural coverage of sequenced genes. Each center must also develop technologies and methodologies that will make the production and structural determination of proteins cheaper, more efficient, and more successful. These large-scale PSI research centers are described in a separate announcement (GM-05-001). o The second component of the PSI Research Network will focus on the development of new methods, technology, approaches, and ideas for protein production and structure determinations for especially challenging proteins, including membrane proteins, small protein complexes, and proteins from human and other higher eukaryotes. These specialized centers will be supported by NIGMS and NCRR. The second component of the PSI Research Network is the subject of this announcement (GM-05-002) and is described in detail below. o The third component of the PSI Research Network will consist of specialized centers that determine protein structures from microorganisms, tissues, or organ systems related to diseases. This third component of the PSI Research Network is being considered as an activity of the NIH Structural Biology Roadmap initiative. o The fourth component of the PSI Research Network is the development and operation of the PSI Knowledge Base. This component will serve as an interface, linking data from the PSI research centers with the PDB and other databases related to the PSI. This information resource will be a hub for the PSI. It will analyze and organize the results from a structural genomics perspective. The NIGMS staff is currently developing a mechanism for supporting this component. o Other related research projects can be added to the PSI Research Network if determined appropriate by the Director of the PSI Research Network. The components of structural genomics are: 1. Family classification and target selection: There are several schemes of protein sequence clustering for parsing proteomes into protein families and for choosing protein targets for structural genomics projects. Target selection for PSI-2 will continue to emphasize the selection of proteins as representatives of sequence families to search rationally for unique protein structures. In the production phase targets will be selected to maximize structural coverage of most sequenced genes, as described below. 2. Generation of protein for biophysical analyses: This includes high throughput cloning, expression, and purification systems to produce large quantities of target proteins in a form suitable for biophysical studies. For PSI, emphasis is on rates of success, efficiency, and cost savings. 3. Sample preparation for structural studies: This crucial experimental task has seen significant progress, with significant improvement in the ability of structural biologists to crystallize proteins and label protein samples for NMR studies. 4. Challenging protein targets: Some classes of proteins are still not amenable to high-throughput operations. These include membrane proteins, protein complexes, and proteins from human and other higher eukaryotes. These classes of proteins are the main focus of this RFA. 5. Structure determination: High-resolution structure determination is becoming straightforward for many protein samples. Crystallography has benefited from the almost universal use of synchrotron beamlines coupled with 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. Applicants for the PSI- 2 specialized research centers must have expertise and resources in either or both of these techniques and are expected to demonstrate their access to state-of-the-art synchrotron and/or NMR facilities as appropriate. The NIGMS is currently developing 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 PSI-2 specialized research centers are expected to present their own plans for data collection and structure determinations. 6. Analyses and dissemination of results: The research centers will be expected to analyze their structures by computational techniques for biomedical significance, including functional characterization and evolutionary and structural relationships. Since the goal of this initiative is to add to the body of knowledge of protein structure, timely release and dissemination of results are crucial. These results include information on strategies for target selections, status of these proteins in the structural genomics pipeline, technological and methodology findings, high throughput approaches, efficiency, and cost analyses. The research centers are required to have plans for timely deposition of coordinates and related data into public databases, consistent with NIH policies and PSI programmatic goals. (See Special requirements.B.1) 7. Management and administration: With several components that are interdependent, management and administration of the center are crucial. In addition to the usual administrative requirements, the leadership of each research center must direct the research and make a wide range of decisions about subcontracts, equipment purchases, staffing, standard protocols, pipeline priorities and protocols, etc. Special PSI requirements, such as cooperative agreement commitments, annual reports, attendance at PSI meetings, participation of minority scientists and students, outreach to the scientific community, research training, intellectual property, participation in the PSI Network, etc., must be incorporated by the applicant into the organization of each research center. Features of specialized centers for technology development: The specialized research centers of the PSI will focus on technology and methodology development to overcome major bottlenecks of the structural genomics pipeline. Emphasis will be on classes of challenging proteins that are not currently amenable to high-throughput methods. These centers will be expected to at least approach high-throughput operation for components of the structural genomics pipeline for these classes of challenging proteins by the end of the project. Success rates, as well as costs and efficiency, are important. Applicants must show that their research will have a major impact on the improvement of this pipeline and the long-range PSI goal of high throughput production and structural determination of all classes of proteins. In addition, applicants must present plans for the development of innovative new methods and technologies which have wide applicability to structural genomics and are both portable and scalable. The specialized centers must have the capability for all components of structural genomics (see list above), but not necessarily in a high-throughput operation. Applicants can arrange to carry out some of the structural genomics tasks through collaborations and/or subcontracts. Another goal, especially in the later years of the project, is the production and structural determination of significant numbers of members of these classes of proteins. Target selection for the specialized centers must emphasize unique, non-redundant protein structures, as described below. The formation of multidisciplinary research teams from multiple institutions and scientific fields is strongly encouraged. Effective plans for management and administration of the research centers are crucial. Rapid release of data into the public databases will be required (See Special requirement B.1). Applicants must describe the major bottleneck(s) to be addressed by their center project and the expected impact. Following discussions with the PSI Advisory Committee members, the NIGMS Council, and members of the scientific community, the NIH staff has identified three major bottlenecks appropriate for these specialized centers. Applicants are encouraged to submit applications for projects that address one or more of these three bottlenecks or other major ones. Topics for specialized centers for technology and methodology development. 1. Membrane proteins. The difficulty of producing and determining the structures of members of this large and important class of proteins is well known. Although the expression of membrane proteins is especially difficult, other tasks leading to structure determination are also hard. Development of innovative methods for protein production (expression, purification, solubilization, etc.), crystallization, and structural determination are needed. The goals of the PSI require a considerable increase in the number of unique membrane protein structures. 2. Proteins from human and other higher eukaryotes. Lower production yields for these proteins have limited the number of eukaryotic structures in the pilot phase of PSI. Problems need to be solved include inadequate cDNA libraries, unknown ligands and cofactors, post- translation modification, etc. 3. Small protein complexes. In many cases, the expression, purification, solubilazation, and crystallization of a protein are unsuccessful without the inclusion of the other member or members of an interacting pair or small complex. Co-expression and co- crystallization are often required for successful structural determination. 4. Other major bottlenecks. Applicants may propose projects focused on other major bottlenecks, but must justify their choice and explain the expected benefits to the PSI. Target selection for PSI-2: Since its inception in 1999, the general principle for target selection for the Protein Structure Initiative has focused on representatives of protein sequence families for which there are no known structures. This approach leads to the determination of unique, non-redundant protein structures and is the policy followed in the PSI pilot phase. Although the target selection policy for PSI-2 begins with this general principle, a more specific policy is required for this subsequent and more focused phase. The NIGMS staff has determined that the best specific strategy for target selection for PSI-2 is to concentrate on large protein families in order to provide the broadest possible structural coverage of sequenced genes. A secondary goal aims directly at biomedical impact with projects focusing on specific pathways, organisms, systems, etc. These conclusions were reached through a lengthy planning process. Prior to the PSI pilot RFA, the NIGMS held a workshop on target selection. More recently, in November 2003, another workshop focused on this issue (http://www.nigms.nih.gov/psi/meetings/target_selection.html ) and a meeting with the PSI Advisory Committee in December 2003 (http://www.nigms.nih.gov/psi/meetings/psi-advisory-centers.html ). At these meetings, most participants agreed on the strategy for structural coverage of sequenced genes by focusing on structural determination of large protein sequence families. Experts from genomic and other biomedical fields discussed the appropriate balance of genomic coverage and biomedical impact. A crucial issue in these discussions was the appropriate level of the detail, or granularity, of structural coverage of sequenced genes. At coarse granularity, sequence homology comparisons are carried out by PSI-BLAST or other profile-based methods to produce protein families with distant evolutionary links. This parsing leads to fewer families, each with more members. As a result, fewer experimental structures will be needed for structural coverage of sequenced genes, and the structural models generated will be moderately accurate for distant homologs in the same family. On the other hand, structural coverage at fine granularity, chosen, for example, as 30% sequence identity, would lead to a larger number of sequence families, each with fewer members. At this fine granularity, more experimental structures will be required, and the computational models generated thereafter would in general be more accurate and suitable for studying biological function. In this workshop and in discussions with the PSI Advisory Committee members, the NIGMS Council, and members of the scientific community, there was general agreement that the primary goal for PSI-2 should the determination of structures representing large sequence families to provide structural coverage at coarse granularity of sequenced genes. A secondary goal of a collection of unique, non- redundant protein structures for specific pathways, organisms, and/or groups of proteins was seen to have high scientific value. Following these discussions, the NIGMS staff has determined that the target selection policy for the PSI should reflect a balance between structural coverage of sequenced genes and the exploration of biomedically important pathways and systems, as described in the previous paragraph. The large-scale centers will be required to address both these goals, providing structural coverage of a majority of sequenced genes by the determination of representative structures of large protein families at coarse granularity and the collection of unique, non-redundant protein structures for structural coverage at fine or coarse granularity of protein families from specific pathways, organisms, and/or groups of proteins of high scientific value. In choosing targets, the large-scale centers will comply with the decisions of the Steering Subcommittee on Target Selection (See Special requirements A.7). Details of the target selection process can be found in the RFA for the large-scale centers (GM-05-001). After the initiation of PSI-2, the Steering Committee and the PSI Advisory Committee will meet jointly with the NIH staff to determine how to carry out target selection for the PSI Network. Further refinement of the target selection criteria by these same groups will occur on a regular basis as the PSI-2 project matures. Target selection for specialized centers: The specialized centers must propose plans for target selection, consistent with the policies described above. Although the primary goal of the specialized centers is the development of methodology and technology for the production and structural determination of challenging proteins, these centers will be required to produce significant numbers of unique, non-redundant protein structures from the class of proteins they have chosen, especially in the final years of the project. Each specialized center must propose a plan for selecting targets for production and structure determination and structural coverage at granularity consistent with the PSI-2 policies and appropriate for its class of challenging proteins. The specialized centers are not directly involved with the target selection process of the large-scale centers, but they will be required to keep the Steering Subcommittee on Target Selection informed of their plans, targets, and structures solved and to participate in the overall planning for structural coverage of sequenced genes. MECHANISM OF SUPPORT This RFA will use NIH Specialized Center (U54, Cooperative Agreement) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The anticipated award date is July 1, 2005. This RFA uses just-in-time concepts. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/master_list.htm. The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". Plans for this program beyond the 5 year award period are indefinite and will be considered by the Institute staff with the advice of the National Advisory General Medical Sciences Council. Applicants can submit applications in response to this RFA for specialized technology centers (GM-05-002) and the RFA (GM-05-001) for large-scale centers and for the RFA for centers for proteins structures related to specific diseases (if the RFA is issued). If an applicant submits more than one of these, the overlap must be clearly noted. Only one award will be made to any applicant. FUNDS AVAILABLE The NIGMS and NCRR intend to commit up to $27 million in FY2005 to fund up to 6 new centers in response to this RFA. An applicant may request a project period of up to 5 years and a budget for the first year of up to $4.5 million total costs. 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 of 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. Post-award management: During the course of the grant period, both computational and experimental technologies are expected to 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. The NIGMS staff must be kept informed of any significant changes. 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 determined by NIGMS AND NCRR staff. In addition, benchmarks for progress may be negotiated annually. The NIGMS AND NCRR 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 AND NCRR 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. ELIGIBLE INSTITUTIONS You may submit an application if your 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 o Domestic institutions/organizations o Foreign institutions are not eligible to apply, but are eligible for inclusion as subcontracts with sufficient justification. 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 A. Special requirements for cooperative agreements 1. Cooperative Agreement Terms and Conditions of Award The following section represents Terms and Conditions that will be incorporated into the award statement and will be provided to the Principal Investigator, as well as to the appropriate institutional official, at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies: The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility for the project as a whole resides with the awardees. 2. Principal Investigator The Principal Investigator is the scientist who assembles the project and is responsible for submitting the application in response to this RFA and for performance of the project. The Principal Investigator has the overall responsibility for scientific and technical direction and for the administration and overall operation of the PSI specialized center. The Principal Investigator will: o Design and direct the specialized center o Design technology and methodology development projects to overcome major bottlenecks of the structural genomics pipeline, with emphasis will be on one or more classes of challenging proteins o Propose plans for selecting targets for production and structure determination and structural coverage at granularity consistent with the PSI-2 policies and appropriate for its class of challenging proteins o Provide goals and milestones for the project consistent with PSI-2 goals o Commit a substantial level of effort to the project o Participate in the cooperative agreement activities and accept PSI-2 policies and plans o Be a member of the PSI Research Network Steering Committee (See Special requirement A.6) o Attend annual meetings of the Steering Committee and participate in its activities, including setting goals and future plans o Serve as liaison to the Steering Subcommittee on Target Selection to provide coordination and assistance in the selection of protein targets o Participate in the activities of the PSI Research Network o Ensure the timely dissemination of information generated by the research center to the scientific public o Ensure that the structure coordinates and structure factors are deposited promptly to the PDB o Ensure that results and data are collected, maintained, and transferred to appropriate databases, including the PDB; the Target Database; and the Protein Expression, Purification, and Crystallization Database o Ensure that all appropriate results are provided to the PSI Knowledge Base o Ensure that the center complies with the intellectual property policies of the research center, the NIH, and those developed by the PSI o Ensure that materials generated by the research center are shared with qualified scientists o Submit periodic progress reports o Appoint an External Scientific Advisory Committee of research scientists not involved in the consortium to provide independent assessment and advice to Principal Investigator and the research center o Manage the Center Development Funds, subject to NIH program director approval. 3. PSI Research Network Director The PSI Research Network Director is an extramural staff individual who has leadership responsibilities for the management and coordination of the PSI Research Network. The PSI Research Network Director is not a member of the Steering Committee and does not direct the scientific activities of the PSI Research Network centers (whose direction is the responsibility of the Principal Investigator). The PSI Research Network Director will also: o Provide advice to the PSI Research Network Steering Committee (See Special requirements A.6) on the overall direction of the PSI and on meeting the PSI goals and milestones o Report on the PSI Research Network activities and progress to the directors of NIGMS AND NCRR, the NIGMS Council, and advisory councils for other participating NIH institutes and centers o Appoint members and a chair of the PSI Advisory Committee, following consultation with the director of NIGMS and other NIH staff o Evaluate and implement the advice of the PSI Advisory Committee and the PSI Research Network Steering Committee for allocating NIH support and revising and setting policy o Facilitate communication with the scientific community directly affected by the PSI o Ensure that the Steering Committee and the PSI Advisory Committee address issues and concerns raised by the community. o Call and coordinate meetings of the Steering Committee and the PSI Advisory Committee o Select appropriate additional programs to be added to the PSI Research Network as non-voting members of the Steering Committee. 4. NIH Program Directors The NIH Program Directors are the extramural staff individuals who provide normal program stewardship for the PSI Research Network center awards. The NIH Program Directors are not members of the Steering Committee and do not direct the scientific activities of the PSI Research Network centers (whose direction is the responsibility of the Principal Investigator). The NIH Program Directors will also: o Negotiate milestones and goals on throughput and costs with the grantees o Attend all meetings of the Steering Committee o Prepare annual reports on the progress of PSI-2 research centers o Provide information to the research center Principal Investigators on activities and policies of the PSI Research Network and the NIH o Recommend appropriate budgets for the research centers, including withholding or reduction of support for failure to meet milestones and/or other terms or conditions. 5. NIH Scientific Liaisons The NIH Scientific Liaisons are representatives of the NIH extramural staff who serve on the Steering Committee and have substantial scientific/programmatic involvement in the project that is above and beyond normal program stewardship. Each of the NIH institutes and centers supporting a PSI Research Network center will have one Scientific Liaison. In addition, one member of the NIGMS staff will serve on the Steering Committee and the Steering Subcommittee on Target Selection. This position will be named the Scientific Liaison for Target Selection. The Scientific Liaisons will also: o Serve as voting members of the Steering Committee and attend all meetings o Assume a substantial coordinating role on the Steering Committee o Make recommendations to the Steering Committee based upon their knowledge of other, related NIH-supported research and resource activities o Facilitate interactions among the Steering Committee, the PSI Advisory Committee, and NIH staff o Provide advice and guidance to the Steering Committee to assure that the PSI project adheres to the NIH rules and regulations o Take on additional responsibilities as negotiated at the time of award. 6. Steering Committee This committee is the main governing body of the Protein Structure Initiative Research Network. Membership will include the Principal Investigators of the large-scale centers, the Principal Investigators of the specialized centers, the NIH Scientific Liaisons, a representative of the Protein Data Bank, a representative of the PSI Research Network Knowledge Base, and other scientists chosen by the Steering Committee. The NIH Scientific Liaisons will serve as voting members of the Steering Committee and attend its meetings. Total NIH representation on the Steering Committee will make up no more than 40% of the voting members. Other members of the NIH staff may also attend the Steering Committee meetings. The Principal Investigators of other related structural genomics projects may be added to the Steering Committee as non-voting members, as determined appropriate by the PSI Research Network Director. The Steering Committee will: o Meet at least annually with the PSI Advisory Committee and the NIGMS staff to discuss progress of the PSI Research Network in reaching the goals set by the NIGMS/NIH staff and Councils and in meeting the needs of the scientific community o Elect a non-NIH chair to serve a 2-year term o Prepare and publish annual reports on progress in meeting milestones and goals of the PSI o Develop procedures and policies on PSI Research Network activities, including laboratory information management systems, data management and deposition, publications, reports, etc. for consideration by the PSI Advisory Committee and the NIGMS Council o Communicate with the scientific community on scientific and technological achievements o Organize and appoint the Steering Subcommittee on Target Selection o Serve as the body for coordinating and making decisions on target selection o Serve as the body for coordinating and making decisions to ensure meeting the milestones and goals for the production phase of the PSI o Organize and appoint appropriate subgroups to address related issues. 7. Steering Subcommittee on Target Selection This subcommittee will be composed of the Principal Investigators of the large-scale centers, the Scientific Liaison for Target Selection, and other representatives as chosen by the Steering Committee. The subcommittee will coordinate the selection of protein targets among the large-scale centers. Representatives of the specialized centers will serve as liaisons to the Steering Subcommittee on Target Selection. Details of this subcommittee can be found in the RFA for large-scale centers (GM-05-001). 8. PSI Advisory Committee The PSI Advisory Committee is a working group of the National Advisory General Medical Sciences Council. It will advise the Council on the management, progress, and plans for the PSI. This committee will: o Meet at least once a year with the Steering Committee and NIH staff prior to the submission of the annual progress report o Examine and comment on target selection policy and progress toward milestones o Provide advice to the Principal Investigators and Steering Committee about meeting the PSI goals and plans for future directions o Raise issues for consideration by the Principal Investigator and the Steering Committee o Comment on the appropriateness of the level of NIGMS support to achieve the goals of the project. 9. Goals and Milestones The PSI-2 will have annual milestones appropriate to the 5-year goal. Milestones will be determined through discussions with the Principal Investigators, Steering Committee, and NIH staff. The milestones and goals will be refined annually with input from the Steering Committee and PSI Advisory Committee. 10. Reports The PSI Research Network Steering Committee will produce an annual report on the progress made toward the annual milestones and goal. The report will be delivered to the NIGMS staff and PSI Advisory Committee within one month of the annual meeting. 11. Arbitration Panel A panel formed as needed to review scientific or programmatic disagreements (within the scope of the award) that may arise between the PSI Research Network and the NIH. It will be composed of three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. (End of cooperative agreement terms) B. PSI Research Specialized Center 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. 1. Data Release and Sharing of Results and Materials. The PSI represents a major scientific endeavor with large amounts of data generated in the process of protein structure determination. The primary products of the PSI, structural coordinates, must be deposited promptly in the PDB, which has served the scientific community for four decades by providing public access to the annotated structural models. Other structural results, including, structure factors, must also be deposited promptly into the PDB. Although guidelines developed by NIH for research grants (http://grants.nih.gov/grants/guide/notice-files/not99-010.html) permit NIH Principal Investigators to deposit coordinates and structure factors upon publication of results, PSI regulations and programmatic goals are more stringent and require these depositions upon completion of the structures. For the start of PSI-2, this will be interpreted as receipt by the PDB within four weeks of the coordinate refinements. In addition, dissemination of results of the research centers is crucial to the programmatic goals of the PSI, and applicants should plan on sharing findings and their 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 reports. These results must be provided to the PSI public website, which contains information on the program and technical and scientific results. Another database, TargetDB (See TargetDB at http://targetdb.pdb.org/), was recently developed by PDB with PSI and contains all the PSI centers targets and weekly progress toward structure determination. This information should avoid duplicative work and assist planning by the centers and other structural labs. The current PSI pilot centers are required to provide these data for uploading each week, and this policy will continue in PSI-2. TargetDB has increasingly attracted attention of the scientific community. The NIGMS is developing a database for deposition of information on experimental outcome data (both successful and unsuccessful). These data include genome analysis for protein clustering and target selection, cDNA cloning, expression vector construction, protein production and purification, protein biochemical characterizations, crystallization screening, synchrotron and NMR data collection, etc. The PSI Research Network centers will be required to provide plans for the collection, maintenance, and transfer of experimental results into this central data repository. This database, named the Protein Expression, Purification, and Crystallization Database (PepcDB), is under development and will contain information on these important results and provide a platform for cross-center data mining to capitalize on the PSI investment (contact Dr. Norvell at NIGMS for updated information). 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 that are beyond the scope of these awards. The research centers will be required to provide these materials to appropriate investigators. Currently the individual pilot centers have the responsibility for distribution of these proteins and samples, but a centralized repository is being considered for PSI-2. In PSI-2, the PSI Advisory Committee and NIGMS staff anticipates the need for a central resource that interconnects all the data and resources generated by the PSI with related databases and other biological information. This resource has been named the PSI Research Network Knowledge Base. The PSI research centers will be required to make all data available for dissemination by the PSI Knowledge Base. 2. Management Plan. The management of a PSI specialized research center requires a significant commitment by the senior staff. The Principal Investigator must 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. If the requested budget includes Center Development Funds (See Special requirement B.9), the applicant must explain how decisions on the use of these funds will be made by the Principal Investigator and the senior staff of the center. 3. Research Training. Applicants are encouraged, but not required, to have plans for research training activities. One example is the involvement of graduate students and postdoctoral associates as part of their research staff. Although many PSI activities involve extensive data collection and therefore might not be appropriate as research training projects, other activities will be at the cutting edge of research and thus would be suitable for graduate thesis research training and for postdoctoral projects. Another example of a research training activity is the organization of technical workshops for graduate students and postdoctoral associates as potential users of the pipeline, materials, and PSI results. 4. Participation of underrepresented minority investigators and students. The research centers are encouraged, but not required, to have plans to promote the participation of investigators and/or students from underrepresented minority groups. One example is organization of summer programs for faculty and/or students from minority institutions. Another example is the solicitation of protein targets from faculty at minority institutions for inclusion in the center’s structural genomics pipeline and target selection process. 5. Participation of the scientific community. The primary responsibility of the specialized PSI centers is the development of methodology and technology for challenging proteins, however they are encouraged, but not required, to have plans for activities for the participation of the scientific community. For example, centers could designate a limited period of time for the incorporation of special projects from outside scientists into the structural genomics pipeline. Centers could plan for short-term courses and technical workshops for potential users of the pipeline, materials, and PSI results. 6. Intellectual property. NIGMS and NCRR are committed to making results of these projects freely available for use by the entire research community and, therefore, released into the public domain. Applicants should present plans related to intellectual property rights consistent with this policy. The NIGMS and NCRR will monitor its grantees' activities with respect to patenting the structural results and technology developments. The scientific review group will comment, as appropriate, on the plans and previously demonstrated success for handling intellectual property issues. Since dissemination of results is a critical aspect of the PSI, evidence of the commitment to the sharing of research resources and to effective management of intellectual property issues will be part of the scientific merit review, as well as an important factor in the Institute’s decision to make an award. Furthermore, these plans, after negotiation with the applicant when necessary, will be made a condition of the award. Evaluation of annual progress reports and of subsequent renewal applications will include an assessment of the effectiveness of the sharing of research resources and managing intellectual property issues. Plans for sharing of research resources and intellectual property must make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps/) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and http://ott.od.nih.gov/NewPages/64FR72090.pdf). These documents also define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. 7. External Scientific Advisory Committee. Each research center should have an external scientific advisory committee of research scientists not involved in the consortium to provide independent assessment and advice to the Principal Investigator and his/her staff. This committee should be appointed by the Principal Investigator of each research center and meet at least once each year. In order to maximize the pool of possible reviewers, the potential (or new) members of the external scientific advisory committee should not be contacted or selected until after an award has been made. 8. PSI Annual Meeting. The Principal Investigator and appropriate staff of each PSI specialized research center will be expected to attend the PSI annual meeting and workshops to discuss progress and results. 9. Center Development Funds. This budget item will provide budgetary flexibility in the development and operation of the structural genomics pipeline for producing proteins and determining their structures. It will permit the specialized centers to make budget changes within a budget year and to explore innovative ideas and new technologies. Since reallocation during any budget year between subprojects (often at different institutions) is difficult, the Center Development Fund may be needed by a specialized center to make major changes and move in new directions. The primary use of these funds must be to support staff and purchase equipment and supplies related to the pipeline tasks. New technology and methodology development projects to improve the structural genomics pipeline are also appropriate. Applicants may request up to 5% of the total budget annually as a Center Development Fund. If these funds are requested, the applicant must describe the process that the center will use to determine its allocation. All expenditures from the Center Development Fund will require NIH staff approval. 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: John C. Norvell, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences Building 45, Room 2AS.13B, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0533 FAX: (301) 480-2004 Email: norvellj@nigms.nih.gov Amy L. Swain, Ph.D. Biomedical Technology Division National Center for Research Resources 6701 Democracy Blvd. Room 964 Bethesda, MD 20892-4874 Telephone (301) 435-0752 FAX (301) 480-3659 Email: SwainA@mail.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Office of Scientific Review National Institute of General Medical Sciences Building 45, Room 3AN.12F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 FAX: (301) 480-8506 Email: sunshinh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Ms. Grace Olascoaga Division of Extramural Activities National Institute of General Medical Sciences Building 45, Room 2AN.32E, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5520 FAX: (301) 480-2554 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. The letter of intent should be sent to: John C. Norvell, Ph.D. Division of Cell Biology and Biophysics National Institute of General Medical Sciences Building 45, Room 2AS.13B, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0533 FAX: (301) 480-2004 Email: norvellj@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: Special application requirements The research center should be an integrated, coordinated project, with various interdependent subprojects that include structural genomics components as described above. These must be fully described and justified. The center must also meet the SPECIAL REQUIREMENTS B.PSI Research Center Special requirements. Collaborations and consortia are encouraged. In such collaborations, the respective contributions should be well integrated into the design of the application. An overview section should be prepared that includes an overall description that defines the scope and objectives. The application should have a face page; abstract; project overview (which describes the overall program and defines its scope and objectives); listing of key personnel; project rationale; subproject descriptions; consolidated budget; subproject budgets; biographical sketches; investigators' other support; institutional support, resources and facilities; and letters of collaboration. The budget should be no greater than $4.5 million total costs for the first year, with annual cost-of-living increases (not to exceed 3%) in subsequent years. The budget should be fully justified and should include funds for attending the PSI annual meetings, workshops, Steering Committee meetings, and other PSI meetings. The page limit for the research plan (including overview, project rationale, and subproject descriptions) is 50 pages total. The application should provide assurances that the center will: o Participate in the activities of the PSI Research Network o Serve on the Steering Committee and assist in target selection, meeting production goals, and planning for the PSI Research Network o Submit data to the PSI Research Network Knowledge Base The application should provide data on protein structures that have been solved by the participating investigators during the past five years. The application should provide data on the production of challenging proteins by the participating investigators during the past five years. The application should describe future plans and past success for: o Methodology and technology development for the class of challenging proteins that are chosen by the center o Producing and determining a significant number of unique, non- redundant protein structures from challenging protein classes o Effective management and administration of a research center or other large research program o Sharing of results and prompt placement of data in the public domain, including deposition of coordinates and structure factors in the Protein Data Bank. The application should describe plans for: o Increasing throughput, efficiency, and success rates and decreasing costs for producing and determining the structures of proteins o Protein family classification and target selection, consistent with PSI-2 policies and appropriate for the class of challenging proteins o Carrying out all the constituent tasks of a structural genomics pipeline o Evaluating the impact of the project on the structural genomics pipeline and the goals of the PSI o Developing annual milestones and evaluations for the center and as a component of the PSI Research Network o Sharing materials generated by this research o Handling intellectual property issues for the center consistent with the NIGMS/NIH policies o Sharing of results and prompt placement of data in the public domain, including submitting target data and progress to the TargetDB, and releasing cloning, protein production, and crystallization results into PepcDB. o Providing resource sharing and training to the scientific community. 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. Office of Scientific Review National Institute of General Medical Sciences Building 45, Room 3AN.12F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 FAX: (301) 480-8506 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 the NIGMS. Incomplete applications will not be reviewed. 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 a written critique 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, provide valuable research resources to the scientific community, 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: Will the technology and methodology development of the research center address the bottleneck chosen by the center? How exportable are the strategies and technologies that will be developed by this center? APPROACH: What is the likelihood that the applicant will operate a successful specialized research center? Are there well-designed plans for developing innovative methodologies and technologies for the production and structural determination of challenging proteins? Is the center likely to produce and determine the structure of a significant number of proteins from classes of challenging proteins? Are the goals, milestones, and organization of the center appropriate? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are plans for protein family classification and target selection, including plans for its applicability to the PSI Research Network, reasonable? INNOVATION: Does the project employ novel and innovative concepts, approaches or methods? INVESTIGATORS: Are the investigators appropriately trained and well suited to carry out this work? Do the investigators have experience and plans for operation of all components included in the structural pipeline? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Does the Principal Investigator have the management, administrative skills, and experience appropriate for a large research project? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of adequate institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: o Plans and assurances that the Principal Investigator will serve on the Steering Committee and assist in target selection, meeting production goals, and planning for the PSI Research Network o Plans for increasing throughput, efficiency, and success rates and decreasing costs for producing and determining the structures of challenging proteins 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 and placement of appropriate data in the PSI Research Network Knowledge Base o Plans for management of the Center Development Fund, if this was requested in the budget. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. (http://grants.nih.gov/grants/policy/data_sharing ) 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: September 10, 2004 Application Receipt Date: October 15, 2004 Peer Review Date: February 2005 Council Review: May 2005 Earliest Anticipated Start Date: July 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, including the uniqueness of the proposed center to the overall goals of the PSI-2. REQUIRED FEDERAL CITATIONS SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 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. 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 PA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: 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)(cite appropriate authorizations) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite relevant regulations). 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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