and Human Services (HHS)
EXPIRED
TOXICOGENOMICS RESEARCH CONSORTIUM Release Date: November 7, 2000 RFA: ES-01-002 National Institute of Environmental Health Sciences http://www.niehs.nih.gov Letter of Intent Receipt Date: February 15, 2001 Application Receipt Date: March 15, 2001 PURPOSE The mission of the National Institute of Environmental Health Science (NIEHS) is to reduce the burden of environmentally associated diseases and dysfunctions by defining how environmental agents affect our health, individuals differ in their susceptibility to these agents, and how these susceptibilities change over time. Recent advances in gene expression analysis using microarray technology have made the assessment of effects of environmental agents on global gene expression possible. The emerging potential of this pioneering technology has clearly shown a capability for revolutionizing the way experiments are conducted and interpreted in the frontier areas of environmental health sciences research. Advancing environmental health sciences research is of enormous importance to NIEHS and, thus, the NIEHS has initiated a national program to develop and accelerate research using microarray technology to assess global gene expression profiles and characteristics associated with physiological mechanisms linking environmental agent exposures to environmental diseases and dysfunctions. The overall NIEHS program has as its goal a coordinated effort to define how the entire genetic complement of an organism responds to environmental agents, including chemicals, physical agents, and physiological stresses. The present Request for Application (RFA) initiative is to develop a national Toxicogenomics Research Consortium (TRC) that will increase the capacity of the extramural research community to apply microarray gene expression profiling to the understanding of biological responses to environmental stress by: 1) accelerating research in the broad area of environmental stress responses using microarray gene expression profiling, 2) developing standards and practices that will allow analysis of gene expression data across platforms and provide intra- and inter- laboratory validations, and 3) contributing to the development of a relational database for gene expression data. It is anticipated that the research outcomes discovered by the TRC will substantially contribute to advancing the development of new approaches for the therapeutic intervention or the prevention of environmental diseases and dysfunctions. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS-led national activity for setting priority areas. This Request for Applications, Toxicogenomics Research Consortium, is related to the priority area of environmental health. Potential applicants may obtain a copy of Healthy People 2010 at http://health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic non-profit and for-profit organizations, private and public, such as universities, colleges, private companies, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. Applications from foreign institutions will not be accepted, however research projects from investigators from foreign institutions can be included as sub-contracts in the proposal submitted by the domestic institution. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Applicants should take note that there are special requirements for responsiveness to this RFA (see Special Instructions for All Applicants), and the criteria for receiving award consideration by the NIEHS (see Review Criteria). MECHANISM OF SUPPORT The administrative and funding instrument to be used for awards resulting from this RFA will be the National Institutes of Health (NIH) U19 Cooperative Agreement. The total project period requested for applications responding to this RFA is five years. A U19 mechanism provides support for both research project components and core facilities. A cooperative agreement is an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIEHS=s role is to support and/or stimulate the recipient=s activity by working jointly with the award recipient as a partner, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the studies to be funded under a cooperative agreement are discussed later in this document under the section Terms and Conditions of Award. There is no intent, real or implied, for the NIEHS staff to direct awardee activities or to limit the freedom of awardee investigators in this regard. Assistance via a cooperative agreement differs from the NIH research project grant in that the government component (NIEHS) awarding the cooperative agreement anticipates a partnership relationship that will enhance the efficiency and effectiveness of an awardee=s efforts. FUNDS AVAILABLE The NIEHS has budgeted up to $5.5 million in estimated total costs to support the first year of all five to six awards made in response to this RFA and $7.5 million is estimated for each of the subsequent four years of awarded support for this program. The NIEHS expects to make at least five to six awards as a result of this RFA. Because the nature and scope of the research posed in applications may vary, it is anticipated that the size of the awards will vary. The number of awards and the level of awarded support depend on the receipt of a sufficient number of applications of high scientific merit. Although this RFA program is provided for in the financial plans of the NIEHS, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Unless otherwise noted, all NIH grant policies apply. This RFA is a one-time solicitation. The NIEHS has not yet determined whether this or a related RFA will be issued in the future to continue the program described in this RFA. The anticipated award date is September, 2001. RESEARCH OBJECTIVES AND SCOPE Background Toxicogenomics is defined as a scientific field that studies how genomes respond to environmental stressors/toxicants. Toxicogenomics combines genome- wide mRNA expression profiling with protein expression patterns using bioinformatics to understand the role of gene-environment interactions in disease and dysfunction. The use of DNA micro-array technologies to assess changes in gene expression is a rapidly growing research area that will have a large impact on many fields, including the environmental health sciences. This technology will allow a paradigm shift in biology and toxicology as it allows a global perspective on how an organism responds to a specific stress, drug, or toxicant. Data generated in toxicogenomic studies will provide information on cellular networks of responding genes that will help define important target molecules associated with the toxicity mechanism, provide biomarkers for epidemiological studies, intensify research on alternative model testing procedures and support the development of new toxicity screening processes. Specifically, experiments using micro-array technology will help define the complex regulatory circuitry within a cell, tissue and organ that is responding to specific stressors. This technology is particularly important because it may be able to help pinpoint locations and time points to effectively intercede in the cascade of biochemical and molecular events perturbed by environmental stressors and, thus, positively modulate the cellular response in a manner reducing or preventing adverse effects. DNA micro-array technology will undoubtedly become a major tool in environmental medicine, for both diagnosis/prognosis determinations for specific diseases or dysfunctions and the examination of interacting drug sensitivities and effectiveness. It is envisioned that DNA microarray technologies will permit the design and execution of research in the environmental sciences that will clarify whether: o specific toxicants have unique gene expression profiling signatures, o different cells in different tissues have profoundly different responses to and signatures for a toxicant, o different animal species show similar, overlapping or distinct patterns of gene responses to a toxicant, o a specific toxicant signature is altered depending upon the stage in the developmental process or defined health conditions, o responses to complex mixtures can be more easily elucidated and defined by their gene expression profiling signatures, o response(s) to chronic low doses of (a) toxicant(s) or environmental pollutant(s) can be defined by gene expression profiling, and o specific gene polymorphisms can be defined that are characteristic of an increased susceptibility to the pathology leading to the morbidity and/or mortality of environmental health diseases or disorders. Objectives The main objective of the Toxicogenomics Research Consortium (TRC) program is to establish a consortium of five or six Cooperative Research Members (CRMs), each with an established research infrastructure and research excellence in gene expression profiling technologies, that will conduct research within the mission responsibilities of the NIEHS as requested in this RFA. The CRMs, operating within the Consortium program will address three main goals: o the enhancement of research in the broad area of global gene expression profiling as it relates to environmental stress responses, o the development of standards and practices which will allow validated data generation and management for inclusion in a public data base, and o contributions of data and expertise toward the development of a robust relational data base of microarray gene expression data. These CRMs will employ gene expression profiling for conducting studies that will elucidate basic biological pathways and their interactions with toxicant exposures, as well as defining how the entire genetic complement of an organism responds to environmental stressors/ toxicants. Environmental stressors/toxicants include: chemicals, physical agents, and physiological stresses. The TRC will also directly contribute to the establishment of common guidelines for proper protocols and practice standards for the analysis of gene expression profiling data across different microarray platforms by contributing samples and data to a centralized resource contractor who will provide RNA analysis and bioinformatics support. NIEHS will support through a Resource Contractor the RNA analysis and bioinformatics support activities associated with the development of the logistics for CRMs contributing to and accessing the relational database envisioned for the overall NIEHS toxicogenomics program. These support activities will be independently put in place by the NIEHS for the benefit and use of the CRMs of the TRC. Research Scope The research scope of this TRC program broadly includes both basic and toxicological research activities. Basic Research: The Consortium members must have a very strong scientific presence in basic research utilizing gene expression profiling technologies and scientific expertise in one of the following basic science areas: cell cycle regulation, signal transduction, biological damage/stress response, cell death control, and developmental/differentiation mechanisms. The research scope of each CRM must be broad enough to span work in two or more of the following organisms: yeast, Drosophilia, mouse, rat, and/or human. Toxicological Research: The scope of the research to be performed by the Consortium members must include a strong presence in an area of toxicological research exploring the mechanism of action of environmental agents that can be investigated using gene expression profiling technologies. DESCRIPTION OF A COOPERATIVE RESEARCH MEMBER. The minimum requirements for the Cooperative Research Member (CRM) described in this RFA are as follows (see also Review Criteria and Procedures below): o Competent and experienced principal investigator who is committed to and directly involved in using gene expression profiling in his or her research. o Availability of competent and experienced project leaders to direct individual research projects associated with the proposed CRM. o Availability of the fully operational technical resources and facilities necessary (core laboratories) for the conduct of the experiments. o Access to properly managed animal facilities for projects conducting animal studies. o Substantive evidence of departmental and institutional support for and commitment to the proposed Research Member. o Documented willingness to cooperate in a coordinated manner within the Toxicogenomics Research Consortium (TRC). o Documented willingness to carry out experimental toxicological studies designed by the consensus process of the TRC Steering Committee to be performed by members of the TRC, including providing materials and data from such toxicological research to the participating TRC members and, as deemed appropriate, to the NIEHS contracted gene expression analysis/bioinformatics support resource. o Documented willingness to deposit toxicologically relevant data into public databases following procedures developed by the consortium in accord with the Steering Committee consensus process and extant applicable NIH grant policies in this regard. o A proposed overall CRM project structure consisting of: (1) a minimum of two basic research projects with a minimum of one aim in each related to toxicology as described in this RFA, and (2) core components representing at a minimum the administrative core, technical facility(ies) core(s) and toxicology research core as described in this RFA. SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS I. Definitions COOPERATIVE RESEARCH MEMBER (CRM): The organized awardee infrastructure supporting a coordinated U19 program of NIEHS mission relevant research being conducted by an organized group of scientists. CRMs consist of three components: basic research projects, a toxicology research core and facilities cores. In addition to the requisite toxicology research core and administrative core, a CRM has technical facilities cores (including a bioinformatics component). TOXICOGENOMICS RESEARCH CONSORTIUM: An interacting consortium group comprised of the five or six U19 Cooperative Research Members awarded as a result of this RFA. COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated to be substantial programmatic involvement by NIEHS scientific program staff with the recipient organization during the performance of the planned activity. AWARDEE: The institution to which the cooperative agreement is awarded. PRINCIPAL INVESTIGATOR: The person who assembles the program, is responsible for submitting the application in response to this RFA, and is responsible for the administrative and scientific performance of the program. The Principal Investigator will also oversee the progress on each of the basic and toxicological research projects, and will coordinate the activities of the projects and cores. NIEHS EXTRAMURAL TOXICOGENOMICS RESEARCH COORDINATOR (ETRC): The NIEHS program staff scientist who coordinates the programmatic involvement of the NIEHS with the CRMs of the TRC. The ETRC is a voting partnership member of the TRC Steering Committee. ARBITRATION PANEL: A panel that is formed to review scientific or programmatic disagreement(within the scope of the award) that may arise between award recipients and NIEHS. It will be composed of three members: (i) a designee of the Steering Committee chosen without NIEHS staff voting, (ii) one NIEHS designee, and (iii) a third designee with relevant expertise who is chosen by the other two (in the case of an individual disagreement, the first member may be chosen by the individual awardee). The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work and that restrict progress. DIVISION OF EXTRAMURAL RESEARCH AND TRAINING WORKING GROUP (DWG): The Division of Extramural Research and Training (DERT) is the extramural program component of the NIEHS that supports extramural research. The DERT Working Group (DWG) is composed of program scientists from the NIEHS extramural program staff. The DWG membership consists of the NIEHS Toxicogenomics Consortium Research Coordinator, and four NIEHS Program Administrators, who have substantial scientific/programming advisory involvement regarding the conduct of the TRC activities. The DWG is chaired by the NIEHS Toxicogenomics Research Coordinator (ETRC) member of the TRC Steering Committee. TOXICOGENOMICS RESEARCH CONSORTIUM STEERING COMMITTEE: The governing oversight committee of the TRC. The TRC Steering Committee consists of the principal investigators and Toxicology Research Core Directors of each of the funded cooperative agreements, the NIEHS Extramural Toxicogenomics Research Consortium Coordinator, one science program staff representative of the NIEHS DERT Working Group (DWG), and one representative of the NIEHS Resource Contractor. Each Steering Committee membership identified in this definition has one vote in the deliberations and actions of the Steering Committee. The Steering Committee will meet on a bi-annual basis to set TRC performance priorities, evaluate performance milestones, and plan for the future coordinated experimental studies of the TRC. The Steering Committee may add non-voting scientific advisors to provide expert opinions on specific subject areas as deemed necessary by its deliberations. II. Terms and Conditions of Award The following terms and conditions will be incorporated into the U19 award statement, and will be provided to the Principal Investigator, as well as the appropriate institutional official, at the time of award. Failure to abide by any of the TERMS AND CONDITIONS OF AWARD pertaining to awardee responsibilities as stipulated, may result in reduction of funding, withholding of support, or suspension or termination of award. These special TERMS AND CONDITIONS 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, NIH, and NIH grant administration policies. A. The administrative and funding instrument used for this program will be the Cooperative Agreement (U19). The cooperative agreement is an assistance mechanism (rather than an acquisition mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and/or stimulate the recipient=s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity supported by a cooperative agreement resides with the awardee for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardee(s) and the NIEHS. B. Awardee Rights and Responsibilities: 1. The Principal Investigator is the scientist who is designated by the awardee institution to direct the CRM project. The Principal Investigator will have primary authority and responsibility to define objectives and approaches, and to plan and conduct the proposed research. The Principal Investigator will assume responsibility and accountability to the applicant institution and to the NIEHS for the performance and proper conduct of the research in accordance with the TERMS AND CONDITIONS OF AWARD. The Principal Investigator of each Cooperative Research Member (CRM) will: o Manage the integration of the specific scientific projects. o Provide leadership for conducting the toxicology research core studies. o Oversee the management of the administrative and facilities core laboratories. o Provide yearly summaries of progress during the bi-annual Consortium Meetings. 2. The Principal Investigator or designated representative will serve as a voting member of the TRC Steering Committee and will attend meetings as scheduled. 3. As stated in the RFA, the Principal Investigator will be responsible for accepting the NIEHS TRC general and targeted goals, procedures, and policies. Included, but not limited to, would be the transfer of gene expression profiling data to a third party, such as a NIEHS contract-based resource, for the purpose of developing and/or utilizing a public gene expression profiling relational database. The TRC Steering Committee will set and evaluate specific yearly milestones for each Cooperative Research Member (CRM) Toxicology Research Core for their generation of data pertaining to the consortium conducted toxicology studies described under the special requirements section of this RFA. 4. Awardees will retain custody of, and have primary rights to data developed under awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. Under the terms of OMB circular A-110, data generated by grantees is now subject to the Freedom of Information Act. Data and procedures for its use developed under the U19 may be considered unique research resources. The policy of the PHS is to make available to the public results and accomplishments of activities that it funds. All awardees must adhere to PHS policy for distribution of unique research resources produced with PHS funding, which was published at: http://www.ott.nih.gov/policy/rt_guide_final.html Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIEHS support: see Acknowledgment of Federal Funding (Section 507) in the Notice of Legislative Mandates Contained in the FY2000 Omnibus Appropriations at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-010.html Dissemination of information, data or substances supplied by NIEHS will require clearance by NIEHS to assure conformity with any existing confidentiality agreements with the primary suppliers of such information, data or substances to the NIEHS. 5. Possessory rights of physical materials acquired during the course of research rests with the applicant. Prior to award, the applicant must formulate a policy for final disposition of such physical materials and ownership rights in the event that such physical materials are transferred to other parties who use them to make discoveries. 6. The NIEHS recognizes that most countries retain interests in physical materials developed during the course of research within their domains. In the event that an applicant includes a foreign project collaboration as a sub- contract in the proposed CRM application, a formal statement of agreement, prior to an award, must be provided to the NIEHS, signed by an authorized representative of the applicant institution and that of the collaborators, if any, for equitable return of any profits or royalties derived from discoveries supported by the CRM award to indigenous peoples, research collaborators, cooperating institutions or governmental entities in the country of origin, as appropriate to their contributions. C. NIEHS Extramural Staff Responsibilities 1. The NIEHS will select one extramural program staff scientist with appropriate expertise to serve as the NIEHS Extramural TRC Research Coordinator (ETRC) for the TRC. During the performance of the award, through the ETRC, the NIEHS will participate in the TRC as a partner in the planning, prioritization, implementation, and technical scientific guidance of the tasked activities developed by the Steering Committee. The ETRC will have one independent vote on the TRC Steering Committee. The ETRC is responsible for providing appropriate scientific and scientific program management assistance to the CRMs in support of and in accord with the tasked activities established by the TRC Steering Committee in its pursuit of fullfilling the obligations of the Terms and Conditions of Award established for each CRM. The ETRC serves as the primary liaison for the TRC with the contracted support services and materials to be independently provided by the NIEHS. It all cases the role of the ETRC will be to provide advisory scientific expertise and scientific program coordination of TRC research activities to assist and facilitate, but not to direct, these research activities. 2. The NIEHS Extramural TRC Research Coordinator, as well as any other TRC group member, may assist in research planning, may suggest studies within the approved scope of the TRC objectives and research activities, may present to the TRC experimental findings from published sources or from contract projects in support of these suggestions, may participate in the design of experiments agreed to by the TRC, may advise on the selection and accessing of sources for resources, may advise in the scientific management and technical performance of the TRC research activities, and participate in the analysis of results achieved by these research activities. The ETRC will not, however, directly conduct laboratory studies in the research activities being performed by the TRC. 3. Upon recommendation of the NIEHS Extramural TRC Research Coordinator, NIEHS may provide a CRM access to physical and/or intellectual resources from NIEHS contracted resources to support appropriate TRC activities when such resources are required to meet the Terms and Conditions for Award for a CRM. The following is a list of resources that may be supplied: a. Reference materials for standardization of analytical systems, as analytical standards, and for related purposes. b. Needed resources to ensure CRM data validation, such as test materials and information. c. Data from testing/analyses conducted in the resource contract laboratory(ies). d. Laboratory testing capacity in an NIEHS contract-based resource. e. Searches of computer files of materials, gene or gene expression profiling, or biological activity in an NIEHS contract supported database in accord with any confidentiality agreement between the Government and the supplier of such material or information. 4. The ETRC will serve as the TRC liaison to the NIEHS= National Center for Toxicogenomics (NCT) Coordination Panel. In this capacity, the ETRC represents and makes presentations on behalf of the TRC to a committee of NIEHS scientists that evaluates the overall effectiveness and achievements of the combined extramural, intramural and contract laboratories contributing to the overall national toxicogenomics program of the NIEHS. The NCT Coordination Panel provides, through appropriate channels, recommendations to the Director, NIEHS, for evaluating future national directions and needs in Toxicogenomics research. The NIEHS reviews such recommendations for a determination for NIEHS actions using a Toxicogenomics Advisory Committee of 20-25 senior extramural scientists with relevant expertise in the fields of toxicogenomics, proteomics, bioinformatics and toxicology, who are not Principal Investigators of a cooperative agreement involved in the Toxicogenomics Research Consortium supported as a result of this RFA. 5. The NIEHS will select one Program Administrator from the NIEHS extramural program staff to administer the cooperative agreement awards for the CRMs of the TRC. The TRC/CRM PA, who is separate and distinct from the ETRC, will provide the NIEHS stewardship of the cooperative agreement awards during the performance of the awarded research activities. The Program Administrator will monitor the adequacy of each individual CRM awards progress annually and provide the usual grant stewardship and administrative assistance for each individual cooperative agreement. The NIEHS retains the option for the TRC/CRM Program Administrator to recommend to the NIEHS Director the withholding or reduction of support or suspension or termination of funding for any project within a CRM of the Toxicogenomics Research Consortium that substantially fails to achieve its gene expression profile milestone goals. The NIEHS also retains the option for withholding or reduction of support or suspension or termination of funding for any CRM cooperative agreement that materially fails to comply with the Terms and Conditions of the award. 6. The NIEHS Division of Extramural Research and Training (DERT) will form a DERT Working Group (DWG) with the following responsibilities. The DERT working group will have substantial scientific and/or programmatic involvement with TRC during the conduct of this activity through technical assistance and technical coordination facilitation of collaborations with the DWG members administered resource sponsored or cosponsored programs of the NIEHS, including the NIEHS Environmental Genome Program, the Mouse Genome Project, the Pharmacogenetics Project and the Metabolic Toxicology Program. However, the role of the NIEHS will be strictly to assist and facilitate and not to direct the activities of the TRC or its CRMs. It is anticipated for the TRC that decisions in all of its coordinated activities will be reached by consensus of the Toxicogenomics Research Consortium Steering Committee and that NIEHS will be given the opportunity to offer input to this process through the Extramural Toxicogenomics Research Coordinator and the DWG. The DWG will be chaired by the NIEHS Extramural Toxicogenomics Research Coordinator and have four other NIEHS staff scientists as members appointed by the Director, DERT, NIEHS. A representative member of the DWG shall participate in the TRC Steering Committee and will hold one vote on behalf of the DWG in the consensus deciding activities of that committee. This vote is independent of the vote of the ETRC described in item number one above. NIEHS staff will not have a majority of the votes in the TRC voting processes. The TCR DERT Working Group will: o Participate through its representative on the Steering Committee with the other Steering Committee members in the group process of setting research priorities, for the prescribed toxicological experiments, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The DWG participation will assist and facilitate the group consensus process and not direct it. o Attend all Steering Committee meetings with representation as a voting member and assist in developing research priorities, operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated actions by a the CRMs comprising a multi- component, highly complex national cooperative research program. o Serve on subcommittees of the Steering Committee, as appropriate. o Assist in promoting the availability of the toxicogenomics data and related resources developed in the course of this project to the scientific community at large. D. Collaborative Responsibilities The Principle Investigators and Toxicology Research Core Directors for the U19 Toxicogenomic Research Consortium (TRC) cooperative agreement awards, the NIEHS Extramural TRC Research Coordinator, one representative of the TRC/DWG, and one scientist representative of the NIEHS Resource Contract will form a Togicogenomics Research Consortium Steering Committee. A chairperson, not from the NIEHS, will be selected by majority vote of the TRC Steering Committee members. The Steering Committee may, when deemed to be necessary, invite additional, ad hoc, non-voting advisors to the meetings. Other NIEHS program staff, as appropriate, may attend the TRC Steering Committee meeting. The TRC Steering Committee may, as deemed necessary, establish tasked subcommittees. NIEHS program staff may serve on these subcommittees. The TRC Steering Committee will meet at least twice annually. One meeting will be at the NIEHS in Research Triangle Park, NC and the second at a time and place agreed upon by the TRC Steering Committee. The TRC Steering Committee will serve as the main governing board of the Toxicogenomics Research Consortium. An arbitration process will be established, as detailed further below, to resolve any disagreement that may arise between NIEHS program scientists and the non-government membership of the TRC Steering Committee. The Steering Committee will be responsible for evaluating tasked activities progress within the Toxicogenomics Research Consortium, overseeing the toxicology research core studies, and monitoring CRM compliance with the Terms and Conditions of Award pertaining to these tasks. The Steering Committee, as a group, will evaluate the data presented by individual Principal Investigators for the tasked activities of their CRM program. The Steering Committee will assist and facilitate the development of uniform procedures for data quality assessment. All CRMs will be required to accept and implement the common guidelines, procedures and standards approved by the Steering Committee in this regard. Members of the Steering Committee will: o accept and participate in the cooperative nature of the group, and o attend bi-annual Steering Committee meetings to review results, evaluate data, check progress toward milestones, and conduct planning and prioritizing activities of the Toxicogenomics Research Consortium. A planning meeting of the TRC Steering Committee will be convened by the NIEHS extramural program staff shortly after the U19 awards have been made. At this meeting, a Chair will be selected and the group may: o draft a charter/operations manual that details policies and procedures and agree on the terms of this charter/operations manual, o determine a plan for scheduling the time and place of future meetings, and o review criteria for the validation of gene expression profile data for contributing data for inclusion in the NIEHS sponsored gene expression profiling relational database. Subsequent meetings will conduct the Steering Committee functions described earlier in this section. In summary, the purpose of the Toxicogenomics Research Consortium (TRC) Steering Committee is to apply its collective knowledge to accelerate the pace of discovery and characterization of gene expression profiles providing an identification of toxicant induced gene signatures associated with environmental disease or disorders. Members of the TRC Steering Committee and their collaborators will participate in recommending guidelines and standards for the discovery and validation of global gene expression profiles of critical importance to environmental health sciences research. Members of the TRC Steering Committee will have the advantage of access to resources, information, technologies, ideas, and expertise in multi-disciplinary areas to facilitate their research. As validated data on global gene expression profiling is acquired, the NIEHS will provide a mechanism to ensure the dissemination of such information to the research community, with appropriate safeguards for the protection of intellectual property. Ideally, the best- case expected outcome from these cooperative, coordinated efforts would be the discovery of toxicant exposure gene signatures useful for designing therapeutic intervention or prevention strategies for reducing or eliminating an environmental disease or disorder. E. Arbitration Panel Any disagreement that may arise on scientific/programmatic matters (within the scope of the U19 award), between award recipients and the NIEHS Extramural Program staff may be brought to arbitration. An Arbitration Panel will be convened composed of three members: one selected by the Toxicogenomics Research Consortium Steering Committee without NIEHS staff voting, a second member selected by the NIEHS, and a third member agreed upon by the other two. For U19 awardees, this special arbitration procedure in no way affects the awardee=s right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research" published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html) A complete copy of the updated guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual and to conduct and report analyses, as appropriate by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects" research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PREAPPLICATION MEETING The NIEHS strongly encourages all potential applicants to attend a pre- application Technical Assistance Workshop (TAW) which will be held at the NIEHS in Research Triangle Park, NC. Since the concept of a cooperative Toxicogenomic Research Consortium is an entirely new concept for the NIEHS and the applicant population, this workshop will provide NIEHS staff the opportunity to clarify any perceived ambiguities in the RFA and, thereby, enable applicants to present their strongest case for support. NIEHS encourages potential applicants to check its web site for future information: http://www.niehs.nih.gov/external/grant.htm LETTER OF INTENT Prospective applicants are asked to submit, by February 15, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 institute staff to estimate the potential review workload and plan the review. The letter of intent should be sent to: Linda K. Bass, Ph.D. Scientific Review Administrator Scientific Review Branch Division of Extramural Research and Training 111 Alexander Drive P.O. Box 12233 Research Triangle Park, NC 27709 Phone (919) 541-1307 Fax (919) 541-2503 email: bass@niehs.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for the U19 grants described in this RFA. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: GrantsInfo@nih.gov The RFA label available in the PHS 398 (Rev 4/98) application form must be affixed to the bottom of the face page of the application. 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 (TOXICOGENOMICS RESEARCH CONSORTIUM) and number (ES-01-002) must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 or BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all the APPENDIX material must also be sent to: Linda K. Bass, Ph.D. Scientific Review Administrator Scientific Review Branch (EC-30) Division of Extramural Research and Training 111 Alexander Drive P.O. Box 12233 Research Triangle Park, NC 27709 Phone (919) 541-1307 Fax (919) 541-2503 email: bass@niehs.nih.gov Applications must be postmarked by March 15, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. SPECIAL INSTRUCTIONS FOR ALL APPLICANTS Applicants must consider and address the following in the preparation of applications called for in this RFA: 1. Specific issues related to cooperative agreements must be addressed as follows: a. Special budget considerations. Applicants must budget (i.e., based on a city centrally located in the USA) for travel and per diem expenses for the TRC Steering Committee meetings. In the first year, applicants should plan for the Principal Investigator, two project investigators, and the director of the Toxicology Research Core to attend two TRC Steering Committee meetings. In the second and subsequent years, applicants should plan for the Principal Investigator to attend two TRC Steering Committee meetings per year. It is anticipated that the coordinated Toxicology Research Core activity will be at a basal level during the first year. Applicants should budget proportionally more funding to the basic research projects and facilities cores in the first year and budget a 25 percent effort of a core director and one FTE technical support position for the Toxicology Research Core Facility in the first year. Applicants should budget proportionally more of the increase from the first year to the second and subsequent years to increase the Toxicology Research Core budget to not less than $100,000 direct cost in years two through five. b. Special research considerations Basic research projects included in the application for a CRM must have AT LEAST ONE SPECIFIC AIM DESCRIBED THAT INVOLVES RESEARCH RELEVANT TO AN EXPOSURE TO A TOXICANT within the research scope described in this RFA (see also item 2b, 2b(i) and 2b(ii) below). Applicants must include their specific plans for responding to the Terms and Conditions of Award section. Applicants should state their willingness to collaborate and share data freely with the other TRC awardees, to participate in planning and to serve on the TRC Steering Committee and be bound by its decisions for setting the standards and guidelines for characterization and validation of global gene expression profiling results, and to be able and willing to share data and communicate with each other and the NIEHS in an internet environment. Applicants should also describe how they would comply with the involvement of an NIEHS Extramural TRC Research Coordinator. 2. Application format to follow a. The format outlined in the form PHS 398 kit should be followed except for the additional materials listed below which should be included in the indicated order after the LITERATURE CITED section. i. An overview of the CRM concept proposed The Principal Investigator should provide a brief discussion (not to exceed two pages) of the functionally integrated concept for the CRM program proposed and how it will be responsive to the goals and objectives stated in this RFA for the Toxicogenomic Research Consortium. ii. Documentation of gene expression profiling accomplishments. The application must contain clear documentation of the applicant=s capacity to successfully and productively perform gene expression profiling technologies. The total length for the presentation of this documentation should not exceed five pages. Brief, concise statements are encouraged. Please focus these statements on past accomplishments, rather than future plans except as noted. For the purposes of this RFA, completed data is defined as gene expression profile data produced in and by the research group included in the CRM application. It is suggested that the following question regarding GENE EXPRESSION PROFILE PRODUCTION be considered in your response. How does your group=s past effort support its ability/capacity to successfully accommodate this toxicogenomics project? Discussion should include, but is not limited to: o Prior experience in hybridization and increasing throughput. o Prior experience in attaining milestones with regard to DNA microarray development (for example chip printing, hybridization schedules, and data analysis throughput). o Cost analysis of DNA microarrays, hybridization, and data analysis in terms of personnel and materials cost on a per unit chip cost. It is suggested that graphical and tabular material may be the best means of presenting some of the relevant information, e.g., - a graph indicating, for the past year (per month), the number and type of chips produced. - a graph indicating, for the past year (per month), the number and type of hybridizations attempted. - a graph for the number and type of analyses performed. iii. A statement of acceptance of NIEHS staff participation as described in NIEHS Extramural Staff Responsibilities. iv. A statement by the Principal Investigator accepting participation on the TRC Steering Committee and implementing, if applicable, the goals, procedures and policies agreed upon by the TRC Steering Committee. b. Format for the CRM The format outlined in the form PHS 398 kit should be followed. The formatting of the application should take into consideration the expectation that a Cooperative Research Member should be structured to include: o Basic Research Projects (two to three minimum). o A Toxicology Research Core (one only) o An Administrative Core (one only). o Facility Cores (as required). i. Basic Research Projects should be organized in the standard PHS 398 format of an R01 proposal with sections for an abstract, specific aims, background and significance, preliminary results, experimental design and methods and references. It is IMPORTANT to note that each Basic Research Project must have one Specific Aim that is directly related to research involving a toxicant exposure that is within the scope of this RFA. ii. The Toxicology Research Core should be organized in the standard PHS 398 format of an R01 proposal. It is IMPORTANT to note that the research to be actually conducted by the Toxicology Research Core will be determined by the consensus process of the TRC Steering Committee during the first year of the awarded CRM. The proposal for the Toxicology Research Core should therefor present a theoretical demonstration project that displays the potential of the research core. The proposal should present a novel research idea to be investigated via a global toxicological gene expression profiling research project and should be organized in the standard PHS 398 format of an R01 proposal with sections for an abstract, specific aims, background and significance, preliminary results, experimental design and methods and references. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the program staff in the Division of Extramural Research and Training (DERT), NIEHS. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. As part of the initial merit review, a process may be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. The scored applications will receive a second level review by the National Advisory Environmental Health Sciences Council. The specific points of consideration for completeness and responsiveness to the RFA are: (1) the appropriateness of the science proposed in regard to the mission of the NIEHS, and (2) the general completeness of the application including responsiveness to programmatic requirements and the organizational adequacy for review (this includes both scientific and budgetary considerations). The specific points of programmatic responsiveness to this RFA include: (1) documentation as requested in this RFA that investigators or groups of investigators in the application have performed and appropriately documented the performance of not less than 75 hybridizations using microarray gene expression profiling technology prior to the submission date for the application,(2) a proposed overall CRM project structure that includes a minimum of two basic research projects with a minimum of at least one specific aim in each project having a translational component to toxicological research (for example, a focus on the mechanism of action of one or more environmental agents), an administrative core that provides administrative services for the CRM, (a)technical facility core(s) providing instrumentation, bioinformatics and statistical support for the research, and a toxicology research core that supports the conduct of TRC coordinated toxicology research projects. To ensure the goals of this RFA can be met, applications not containing the indicated hybridization documentation and/or overall CRM project structure described above will not be accepted by the NIEHS. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Research and Training of the NIEHS in accordance with the review criteria stated below. REVIEW CRITERIA FOR THE EVALUATION OF THE OVERALL PROGRAM APPLICATION The overall program application is evaluated by considering the research projects, supporting cores, and the administrative structure, and how these multi-disciplinary components function together to achieve the goals of the TRC program. For the application to receive an overall priority score, it must consist of at least two approved research projects, each of which has multiple specific aims with at least one specific aim addressing a toxicological research issue and one Toxicology Research Core (found to have significant and substantial merit) for the full five year duration of the project period. Specific scientific consideration factors to be evaluated in the consideration of the program are as follows: o Scientific merit of the program as a whole, as well as that of the individual parts. o Significance of the overall program goals. This includes the significance and importance of the research program to furthering knowledge of gene expression profiling in environmental health sciences. o Scientific gain of combining the component parts into a CRM. The appropriateness of the size of the program is an important consideration. o Cohesiveness and multidisciplinary scope of the program and the coordination and interrelationships of all individual research projects and cores to the common theme of using and improving gene expression profiling for biology and toxicology research via advances using applied microarray technologies. o Leadership and scientific ability of the principal investigator and his or her commitment and ability to develop a well-defined central research focus and to devote adequate time and effort to work within the parameters of the TRC consortia. o Past accomplishments of the research team (Principal Investigator, Project and Core Leaders)in the proposed, including demonstrable experience of not less than 75 hybridizations for the application of gene array profiling to address biological issues. o Environment and resources in which the research will be conducted, including availability of space, equipment, human subjects, animals, or other resources as required, and the potential for interaction with scientists from other departments. o Institutional commitment to the requirements of the program, including fiscal responsibility and management capability of the institution to assist the Principal Investigator and his or her staff in following DHHS, PHS, and NIH policy. REVIEW CRITERIA FOR INDIVIDUAL RESEARCH PROJECTS The review of the individual Research Projects is similar to the review of individual project grant applications (RO1). Accordingly, these projects must have substantial scientific merit. The review criteria (Significance, Approach, Innovation and Environment) are intended to encourage reviewers to focus on the global impacts of each project and the program overall, rather than concentrating on the experimental details and their critiques. The review criteria are as follows: o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o 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? Does the project make maximal use of microarray technology to achieve its goals? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new, methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? o 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 institutional support? o When human subjects are involved, the adequacy of plans to include women and minorities in the study design and the potential of that design to address scientific question(s) proposed must be addressed. REVIEW CRITERIA FOR INDIVIDUAL TECHNICAL FACILITY CORES o Utility of the core to the CRM, each core should provide essential facilities or service for two or more projects judged to have substantial merit (e.g., the number of projects that will benefit from centralized administrative and research services, the economy of effort that will be realized through use of shared services, etc.) o Quality of the facilities or services provided by this core (including procedures, techniques, and quality control) and criteria for prioritization of usage. o Qualifications, experience and commitment of the personnel involved in the core. o Appropriateness of the budget. REVIEW CRITERIA FOR THE TOXICOLOGY RESEARCH CORES o The general criteria for a technical facility core (immediately above) apply. In addition, the following specific criterion also applies. o The scientific merit of a hypothetical prospectus project constructed to demonstrate how this toxicology research core would conduct a toxicological research project using gene expression profiling to investigate the environmental stress effects expressed in a biological system exposed to a defined toxicant. REVIEW CRITERIA FOR THE ADMINISTRATIVE CORE For all applications, in addition to evaluating the scientific components, the review will also assess: o Administrative planning and leadership capability to provide for internal quality control of ongoing research, the research needs of the consortia, allocation of funds, enhancement of internal communication and cooperation among the investigators involved in the program, communication with the consortia, and replacement if the principal investigator if required on an interim or permanent basis. o Appropriateness of the budget in relation to the proposed core. o The decision making process within the proposed program for the evaluation of research productivity, allocation of funds, and management of the resources. o Whether the administrative core promotes joint planning and evaluation activities as well as collaborations and interactions among different research cores of the program. SCHEDULE Letter of Intent Receipt Date: February 15, 2001 Application Receipt Date: March 15, 2001 Peer Review Date: June/July, 2001 Council Date: September, 2001 Earliest Anticipated Award: September, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review), o programmatic priorities, and o availability of funds. An award will not be able to be offered for applications that do not have the following approved application components as a result of the peer review outcome: o a minimum of two approved basic research projects, and o an approved Toxicology Research Core. It should also be noted that Facilities Cores that do not serve at least two approved research projects will not be able to be funded as independent cores. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Michael E. McClure, Ph.D. Chief, Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-5327 Fax: (919) 541-5064 E-mail: mcclure@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Jackie Russell Grants Management Specialist Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-0751 Fax: (919) 541-2860 E-mail: russell@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.866. Awards are made under authorization of the public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public law 99- 158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of tobacco products. In addition, Public law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, a 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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