INTEGRATIVE NEUROSCIENCE INITIATIVE ON ALCOHOLISM Release Date: January 22, 2001 RFA: RFA-AA-01-002 (Notice of Limited Competition Request for Applications, see NOT-AA-06-101) National Institute on Alcohol Abuse and Alcoholism ( Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: April 27, 2001 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites applications for a Consortium for the Integrative Neuroscience Initiative on Alcoholism (INIA). This initiative will support highly integrated multidisciplinary research across different research institutions to elucidate the neurobiological mechanisms underlying various aspects of neuroadaptation to alcohol (reinforcement, tolerance, sensitization, withdrawal and relapse). This multidisciplinary initiative will integrate neurobiological, behavioral, and molecular genetic approaches to determine how these aspects of neuroadaptation ultimately contribute to excessive alcohol intake. Furthermore, the initiative will integrate existing resources within the alcohol research community and will also create new resources that are crucial for the success of the research questions being addressed under this initiative. INIA will also provide opportunities for collaboration between scientists in the alcohol field and prominent investigators from other research areas, resulting in the application of new ideas and technology to the study of neuroadaptation to alcohol. 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, Integrative Neuroscience Initiative on Alcoholism, is related to the priority area of alcohol abuse and alcoholism reduction. Potential applicants may obtain a copy of "Healthy People 2010" at: ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. The Consortium Coordinator’s application (lead application) and the core applications have to be from domestic organizations or institutions. However, foreign institutions may be eligible as principal applicants of one or more of the participating sites for the research project components within the consortium. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be multiple cooperative agreement mechanisms (U01and U24). These are assistance mechanisms (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." FUNDS AVAILABLE The NIAAA intends to commit approximately $10,000,000 in FY 2001/ 2002 to fund one or more consortium or cluster of new cooperative agreements in response to this RFA. An applicant may request a project period up to a maximum of 5 years support. There is a cap of $5,000,000 in direct costs for each consortium or cluster of applications responding to this RFA for the first year budget period (with a maximum increase in cost in subsequent years of three percent). Because the nature and scope of the research proposed in response to this RFA might vary, it is anticipated that the size of awards will vary also. Although this program is provided for in the financial plans of the NIAAA, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of applications of outstanding scientific and technical merit. Funds provided under this program may not be used for the purchase of land, nor for the purchase, construction, preservation, or repair of any building. However, costs of alteration and renovation of existing facilities necessary to accomplish the objectives of the grant may be allowed subject to NIH grants policy limitations and approval by NIAAA staff. This RFA is a one-time solicitation. The total project period for an application submitted in response to this RFA may not exceed 5 years, with an anticipated award date of September 28, 2001. In addition, meritorious Research Components from other Consortium applications not funded may be added to the funded consortium at the discretion of NIAAA and taking into account budget limitations and input from its National Advisory Council. RESEARCH OBJECTIVES, SCOPE AND ORGANIZATION NIAAA recognizes the innovation, synergy, and conceptual advances that arise from interactions across scientific disciplines, methodologies, and levels of analysis. It is anticipated that under this initiative knowledge will be generated and integrated from all levels of analysis using state-of-the-art techniques at each level. Neuroscience expertise has become so sophisticated at any given level of analysis that integration at the level of individual investigators becomes very difficult to accomplish, particularly to a level of analysis outside of their domain. The INIA initiative would induce such integration and significantly speed up the translation of such critical new information to the clinical condition. The incorporation of groups of scientists into a research consortium focused on the neuroscience of alcoholism will also offer additional advantages. The rapid and detailed exchange of information among INIA members will provide immediate opportunities for applying the Consortium expertise to profitable research arenas. The success of the proposed initiative will thus relate to the presence of research expertise that uses the full gamut of molecular, cellular, neurochemical techniques, neurocircuitry and neural network expertise, animal genetics, animal behavior and psychopharmacology to study the neuroscience of alcoholism. Thus, information flowing both from the most basic molecular level to the behavioral level and back again can be melded into optimally productive research protocols at multiple levels of endeavor with the focus on the neurocircuitry of excessive alcohol intake. Organization The following structure of INIA is envisioned. The INIA Consortium will consist of a cluster of integrated cooperative agreement research applications (U01s) and a set of five distributed core facilities (U24s) and will be led by a Consortium Coordinator (CC). A highly integrated multidisciplinary research consortium will thus be formed from groups of investigators (within and across institutions) whose scientific and technical expertise will enable them to interactively study the neuroadaptive effects of ethanol from the molecular through the cellular and neural network levels to well characterized and validated behavioral models. The approaches used will reflect the blend of experience and creativity of the INIA components and will be originated by these investigators. Through formation of INIA, the integrated research project component groups will have access through the core facilities to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research team. In addition, the consortium will recruit neuroscience expertise and approaches currently outside the realm of alcohol research and establish state-of-the-art research resources and information networks for alcohol research. The Consortium Coordinator is the scientist who assembles the integrated and collaborative research consortium and is responsible for submitting the cluster of applications in response to this RFA and for performance of the project. The consortium coordinator must be recognized in the area of alcohol research, especially in one of the three interactive research areas or domains of INIA described below. Because a substantial level of effort will be necessary to manage a project of this magnitude, the Consortium Coordinator is expected to make a major commitment to directing, managing and executing the goals and collaborative nature of this project. The Consortium Coordinator application will be the lead application of the consortium and should include the Administrative Coordinating Core, together with the Administrative Management Plan, Plan for Data Sharing and Intellectual Property and the Pilot Project Component (more details are given elsewhere in this announcement). The lead application should discuss the theme and goals of the consortium and should include a scientific rationale for the various research project component and resource core applications that make up the consortium. It should further describe the benefits of the proposed integration between projects and how the individual applications complement each other to enhance the scientific goals of the consortium. Given that an important element of this initiative is the collaboration between leading scientists in the alcohol field and prominent investigators from other fields, the lead application should also discuss how the consortium has achieved that goal. It should describe how these investigators not previously active in alcohol research will participate in either the research project components or the resource core facilities applications of INIA. The lead application should also include a composite budget of the whole consortium in addition to its own individual budget. It is acceptable for the consortium coordinator to submit a research project component or a resource core application in addition to the lead application. While each application (U01 or U24) will originate from the principal investigator(s) research institution and awards will be made to individual institutions, it is the responsibility of the consortium coordinator to submit the cluster of applications of the consortium together with the appropriate cover letter as one package (See Application Procedures and Application Submission Section). Research Project Components Specific research project components to be undertaken under the consortium will take the form of U01 grant applications and are expected to be integrated with the other research projects of INIA. These research project component applications are expected to address at least one of three research areas or domains, namely behavioral, neural circuitry or molecular research domains (discussed in more detail below). It is anticipated that several of the U01 applications within the consortium will address the same research domain, but will differ in emphasis, approaches and research questions being addressed. Research project component applications can request a maximum support period of five years. Applications should include a detailed budget and must follow the traditional PHS 398 application instructions. The U01 research project component applications must utilize the resources and the new technologies developed of one or more resource cores (U24) at one or more sites and advance the scientific goals of INIA. However, the research undertaken by a research project component can be performed at a research site other than the one housing the core site. Exploratory and development projects will also use the U01 mechanism but will be limited to three years of support and with a maximum budget of up to $100,000 direct costs per year. Behavioral Research Component. This component will be responsible for the design and validation of behavioral paradigms for use by INIA. In addition to existing models for sensitization, tolerance, dependence, withdrawal, recovery, and relapse, additional behavioral/neurobiological models require development, validation, and refinement for specific, alcohol-related neuroadaptive phenomena. These animal models may include models of inherent excessive drinking, excessive drinking driven by dependence and acute abstinence by protracted abstinence, by loss of satiety control, and models of vulnerability to relapse. Separate models may be needed for mouse, rat, and non-human primates, depending on the specific phenomenon being studied and the appropriateness of the animal. The component will also choose environmental conditions influencing neuroadaptation, as well as genetically- based strain differences. Genetically-based models can use naturally occurring genetic variation (e.g., selective breeding, congenic strains generated from QTL mapping studies) or artificially induced mutations (e.g., targeted or random mutagenesis). These models will provide the bases for interactive collaborations with other components of INIA. Proper design of studies using genetically based models will require intimate collaboration between investigators with behavioral and genetic expertise, respectively. These investigators may reside either in this component, or in the Animal Models Core (see below). Neural Circuit Research Component. This component will identify and analyze neural circuits employing advanced electrophysiological, neurochemical, and anatomical techniques underlying the various neuroadaptive responses to alcohol. Research is required using multicellular/multiregional techniques in behaving animals to identify and map neural connections within circuits, to study changes in properties of cells, receptors and ion channels within the circuit that occur with ethanol-induced neuroadaptation, and to demonstrate how these responses contribute to excessive alcohol consumption. Because alcohol-induced neuroadaptation may result in changes in synaptic morphology in relevant neural circuits, anatomical techniques will be needed to assess synaptic density and size and number of dendrites. In addition, once neurons have been identified whose activity correlates best with the behavioral state being studied, neuroanatomical pathway tracing protocols, such as those employing horseradish peroxidase and pseudorabies virus as tracers, will need to be used to identify intranuclear projections of those neurons or internuclear connections along the neural circuit. Confocal fluorescence microscopy or other high-resolution optical imaging techniques to map neural circuits and pathways can be used in combination with neurophysiological recording techniques, to identify changes in excitability and neuronal communication within identified neurons during neuroadaptation. The results found will be integrated with gene expression studies. Lastly, approaches developed from computational neurobiology will be used to model neural networks, and in an iterative process, identify new avenues of research. Molecular Research Component. This component will identify the molecular changes induced by ethanol in the neural circuits identified by the Neural Circuits Component. Studies could include receptors and subunit changes and signal transduction pathways, looking for common elements that might stimulate neuroadaptive changes. An important element of the research is to find specific proteins responsible for the induction and maintenance of alcohol dependence. This may require developing innovative new molecular approaches to study neuroadaptation to alcohol exposure. Resource Core Facilities To support the Components of the Consortium, five distributed core resources (U24s), each of which can be located at multiple physical sites, will be needed by INIA. The Animal Production, Gene Expression, Imaging and Informatics Cores will provide facilities for central processing of information generated at different levels of analysis. This information will be shared by the Research Components through the Informatics Core. The power of such an approach is immense, and it will require a strong integrative arrangement. It is possible that some of the core facilities would have multiple sites. For example, under the Animal Production Core one site could be devoted exclusively to mice, whereas another geographically different site could be devoted to rats. In this case, an application (U24) should be submitted from each of the sites with a detailed scientific rationale and budget for that core site. The consortium coordinator should clearly detail, as part of the Administrative Management Plan, the number, location and specialties of the sites comprising every core facility. Each core component is expected to be directed by an investigator with established expertise relative to the support or service provided, usually a faculty-level individual. Administrative Coordinating Core. The Administrative Coordinating Core will provide the organizational framework for the management, direction, and overall coordination of the consortium. It will coordinate use of core resources to the Research Project Components and will acquire and direct data from the Research Components to the Informatics Core. The consortium coordinator will manage the administrative core. The Administrative Coordinating Core will include an Administrative Management plan (See below) and this core will also be responsible for the collaborative responsibilities such as the functions of the Scientific Advisory Panel and the overseeing of a Steering Committee to help develop interactive protocols, evaluate results, and suggest future directions. The core will also administer the Pilot Projects Component of INIA (discussed below) as well as the sharing of data and information between the INIA components. This core is responsible for scientific enrichment activities such as workshops for the researchers and investigators of INIA. In addition, the core will be responsible for organizing an annual meeting of the INIA investigators. Animal Production Core: This core will provide genetically altered animals to the Research Project Components. They can be acquired from outside INIA or developed within INIA by the use of techniques such as targeted mutation or random mutagenesis. Whereas mutants created by random mutagenesis with altered alcohol-related behavior are not yet available, NIAAA has funded screens to generate such mutants, and encourages investigators to use these mutants as they become available for their studies of behavioral and neural adaptation to alcohol. The most recently developed knockout methods disrupt the gene only in a restricted set of tissues rather than in the whole animal (tissue-specific knockouts), or disrupt the gene by precisely timed delivery of a chemical inducer (inducible knockouts). NIAAA encourages investigators to employ these more sophisticated technologies. Although reliable methods for germline modification in the rat are not yet available, they are under active development. INIA applicants should document (now) their readiness to apply these methods as they become available. Gene Expression Core: This core will be responsible for the High-Throughput Gene Expression Assays (cDNA and Oligonucleotide Microarrays) and high- throughput protein arrays. It will establish facilities which could utilize commercially available as well as custom-made microarrays for mRNA expression. It will also have the capabilities of manufacturing and distribution of custom cDNA and oligonucleotide-based arrays on glass or plastic slides for use by the consortium researchers. It will also be responsible for standardizing arrays for comparison of data among different research groups as well as maintain a repository of the alcohol-related expression data of INIA projects. It will also develop and implement techniques for data retrieval, distribution storage and analysis in the Informatics Resource Core of INIA. Lastly, it will begin developing the technology and the resources in the area of proteomics. Imaging Core. This core will provide imaging services to the components. It will develop small animal imaging techniques for in vivo studies. The core will focus on multiple imaging technologies for small animals, emphasizing, but not limited to, those technologies which can provide biochemical, genetic or pharmacological information in vivo. Technology research and development of innovative new imaging technologies appropriate for small animals, as well as refinement and development of technologies already established will also be an additional focus of this core. The future of MR for animal and human studies will ultimately incorporate "molecular imaging" which could involve the tagging of gadolinium-coated liposomes or dextran-coated iron particles with molecules that bind to surface cell receptors. Informatics Core. This core collects and stores data generated by the Research Project Components and will provide an interactive user interface for all components. It will devise methods for integrating data from different levels of analysis from the molecular to the behavioral levels. In addition, it will be responsible for creating a database for alcohol-related proteomics research data as well as gene expression data generated from multiplex hybridization array assays. With the establishment of these databases, there is also a need for additional refinement of bioinformatic tools (such as developing interoperable informatics software packages) to facilitate extraction and efficient dissemination of information from these databases. Consistent with NIH policy ( and, it is expected that the databases developed will be available for use by non-INIA investigators. Applicants will need to develop a plan to be approved by the Institute indicating how they will comply with the policy. OTHER ELEMENTS OF THE INTEGRATED AND COLLABORATIVE PROJECT INIA Administrative and Project Management Plans: The Consortium Coordinator must include an Administrative Management Plan that outlines the policies and procedures for access of participating investigators to the collaborative project resources. The application should address the flow of information within the project, the integration among individual projects and plans for how the information will be integrated into the solution of the overall scientific theme or question being addressed. The application must include a Project Management Plan, including an ongoing evaluation plan, to ensure consistent forward progress of the project. The mechanism to add new participating investigators and dealing with members whose association with the project has not been productive should be documented in the proposal. The plan should also include proposed methods for information dissemination both within the collaborative project and to the scientific community. Furthermore, the application will include a mechanism to consider and respond to concerns of the scientific community directly affected by the operation and impact of the project. A discussion of scientific community views will be part of the agenda for annual meetings of the Steering Committee with the Scientific Advisory Panel. Plan for Data Sharing and Intellectual Property: NIH requires applicants who respond to this RFA to develop and propose specific plans for sharing the data and materials generated through the large-scale collaborative project. This requirement addresses the interests of the Government in the availability of, and access to, the results of publicly funded research. The initial review group will comment on the proposed plans. In addition, as one of the criteria for award, NIAAA staff will also consider the adequacy of the plans. Because dissemination is a critical and important aspect of this RFA, the proposed sharing and data release plans, after negotiation with the applicant when necessary, will be made a condition of the award. The members of the consortium should disclose to the Steering Committee their ties to profit-making organizations to aid the project in avoiding conflict of interest situations. Applicants are also reminded that the grantee institution is required to disclose each subject invention to NIAAA within two months after the inventor discloses it in writing to grantee institution personnel responsible for patent matters. Pilot Project Component: Pilot projects provide the consortium with a flexible means to develop and explore quickly new research activities or directions, and unique scientific opportunities that could evolve into independently funded research projects. These funds are not intended to supplement ongoing projects. Pilot projects must be in a separate pilot project component that incorporates all of the pilot studies of the proposed consortium and should be included in the consortium coordinator’s application. The total costs for the Pilot Project component should not exceed $400,000 per year. The process for selecting pilot projects should be fully, though concisely described. For the first 2 years that funds are requested for pilot projects, the application must provide descriptions of the projects to be supported. It is recognized that for years 3-5, it may not be possible to provide comprehensive descriptions of the pilot projects to be supported, since some of these projects will develop on the basis of scientific breakthroughs or directions occurring at the time. However, the application must provide the specific number of pilots planned in each year. While the specific number of pilot projects to be proposed is at the discretion of the Principal Investigator, requested direct cost funding for each pilot study may not exceed $50,000 per year. All proposed pilot projects need not be ongoing at any one time, but may be phased in at different points during the course of the proposed consortium. It is recognized that the relative priority or need for specific pilot projects may change over time. While the consortium’s framework for management of pilot funds and the mechanism for operating the program are left to the discretion of the Program Coordinator, the application must provide specific information to enable adequate scientific evaluation by a peer review committee. The application should include: a full description of the management of the pilot project component, including a description of the process to be followed by the consortium’s program coordinator in selecting new pilot projects and replacing projects should it become necessary. A full description of each pilot study proposed in the first 2 years will include its rationale, objectives, approach, investigators, and significance for the consortium. A description of the number and anticipated direction of pilot projects in the 3-5 years will be provided including their significance to the consortium. The research description of any individual pilot project may not exceed five pages, the entire narrative for this Pilot Project Component may not exceed 25 pages irrespective of the number of pilot projects proposed. SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS Terms and Conditions of Award The following Terms and Conditions will be incorporated into the award statement and will be provided to the consortium coordinator, to the principal investigators of the individual research components and core facilities, and to the appropriate institutional officials 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 NIAAA programmatic involvement with the awardees is anticipated during performance of the activities. Under the cooperative agreement, the NIAAA supports and stimulates 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 resides with the awardees for the project as a whole. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Awardees should comply with their institutional intellectual property policies and practices as approved in the award. However, awardees will be expected to share (make available) these data openly with the scientific community. 1. Investigator Responsibilities A. Consortium Coordinator’s Responsibilities: The consortium coordinator will coordinate project activities scientifically and administratively at the awardee institution. The consortium coordinator will have the overall responsibility for the scientific and technical direction and the administration and overall operation of the consortium. To assist the consortium coordinator with the governing of the project, a steering committee will be established from among the participating investigators and NIAAA staff. The consortium coordinator will chair the steering committee. As for all participating investigators, the consortium coordinator must abide by the operating rules and guidelines developed by the steering committee. The consortium coordinator will agree to accept participation of NIAAA staff in those aspects of management of the project described under "NIAAA Program Official’s Responsibilities." The consortium coordinator will also ensure the timely dissemination of information generated by the consortium component projects to both the consortium project members and the scientific public. B. Participating Investigator Responsibilities: In addition to the consortium coordinator, as well as principal investigators (PIs) of individual research project components and core facilities of the consortium, each research project component will include a team of investigators who will contribute to and benefit from participation in the consortium. These members of the consortium will be referred to collectively as participating investigators. They will receive separate awards and have control over their own operating budgets. The PI of the individual research project award and the resource core award will be responsible for the scientific and technical direction of the project, as well as for following consortium policies and rules. Participating investigators must also agree to abide by the policies and rules set up for the collaborative research consortium. It is expected that over the period of the award, additional applications for participation in the consortium will be submitted to NIAAA for review and award consideration, as deemed appropriate by the consortium coordinator and steering committee and with the approval of the NIAAA program official, these additions will be reported in the annual progress report. 2. NIAAA Staff Responsibilities The NIAAA Program Official and the two Staff Collaborators will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees, the NIAAA Program Official, and the Staff Collaborators. The two NIAAA Staff Collaborators will have voting membership (one vote) on the Steering Committee and, as determined by that committee, its subcommittees. The NIAAA Staff Collaborators will coordinate and facilitate the INIA Consortium programs, will attend and participate as a voting member in all meetings of the INIA Steering Committee, and will provide liaison between the Steering Committee, the INIA Consortium, and the NIAAA. The NIAAA Staff Collaborators will assist the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action. The NIAAA Program Official will review the scientific progress of individual components, and review them for compliance with the operating policies developed by the Steering Committee, and may recommend withholding of support, suspension, or termination of an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. 3. Collaborative Responsibilities Scientific Advisory Panel The INIA project will include an external scientific advisory panel whose purpose is to meet annually with the consortium coordinator and the steering committee to assess progress and provide feedback to the INIA investigators and NIAAA on proposed goals for the next year of support. The members will be designated by the NIAAA in consultation with the steering committee, after the award has been made, and will be drawn from research scientists not involved in the project. The NIAAA staff collaborators will attend the meeting of the scientific advisory panel as members of the steering committee, but will not be members of the scientific advisory panel. The scientific advisory panel will meet at least once a year immediately prior to the submission of the annual progress report. Steering Committee The NIAAA staff collaborators and the awardees that comprise the INIA will be responsible for forming a Steering Committee as defined below. The Steering Committee will be the main governing board of the INIA. It will develop collaborative protocols, and function to set priorities for model derivation, define the parameters for model validation, identify technological impediments to success and strategies to overcome them, and decide when models should be made available to the research community for individual investigator-initiated projects. The Steering Committee will be composed of the consortium coordinator, principal investigators of the research project components and core facilities, and the NIAAA staff collaborators. The members of the Steering Committee will each have one vote. The chairperson of the steering committee will be the consortium coordinator. NIAAA reserves the right to appoint additional members of NIAAA staff as nonvoting members of the INIA Steering Committee and Subcommittees. The Steering Committee may, when deemed necessary, invite additional, non-voting scientific advisors to the meetings at which research priorities and opportunities are discussed. NIAAA reserves the right to augment the scientific or consumer expertise of the INIA Steering Committee when necessary. There will be two Steering Committee meetings initially (during the first two years of support), one in the Washington, D.C. area, and the other at a time and site agreed upon by the Steering Committee and the NIAAA. In years 3-5, the Steering Committee will meet once a year. The first meeting of INIA will be a Planning Meeting, which will take place in the Washington, D.C. area very shortly after award of the grants. At the Planning Meeting, the Committee will: a) determine the size of the Steering Committee and the representation of individual research project and resource core awardees on the Steering Committee, b) draft a charter, the purpose of which is to define the administrative policies and procedures for oversight of the project, the process for monitoring compliance with those policies and procedures, and the process for recommending that the NIAAA act on evidence of non-compliance of any consortium component with Steering Committee policies, c) agree upon the terms of the charter, d) discuss the models and approaches that were proposed in the individual component and core applications, any relevant new information, and set initial priorities for the models to be derived and for new technologies to be developed, and, e) discuss and set initial standards for validating the models for further biological studies. At their first meeting each year, the Steering Committee will formulate plans for any new pilot projects to be funded. They will discuss projects to be pursued jointly with funds set aside from the pilot projects budget. At subsequent meetings, the Steering Committee will refine the scientific objectives and characterization and validation strategies of INIA, as necessary, consistent with progress in the INIA consortium components and other laboratories, and with the goals of identifying available models with sufficient promise for further analysis. At any time during the INIA project, the Steering Committee may examine the characterization and validation data for models derived by the INIA consortium components, and decide when a model is sufficiently validated that it may be distributed to the research community for further investigations or applications. The NIAAA will provide the means to disseminate the models themselves and the information related to them. The Steering Committee will plan one or more workshops a year to which non-INIA participants will also be invited to enable the INIA consortium to explore scientific or technologic innovation that occurs during the course of the project. For the second and subsequent years of operation of the INIA consortium, the Steering Committee will plan a symposium to inform the research community of the progress made toward derivation or refinement of models, their characterization and validated uses, and any technological advances related to design and derivation of these models. The NIAAA Program Official and other NIAAA staff will provide the Steering Committee with advice on participants for the workshops and symposia, and manage the logistics for these meetings. The Steering Committee may establish subcommittees as it deems appropriate. The NIAAA Program Official and the other NIAAA/NIH staff who are Steering Committee members may serve on subcommittees. Awardees will be required to accept actions and recommendations approved by the Steering Committee. 4. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the collaborative mechanism award) between U01 and U24 awardees and the NIAAA may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIAAA Program Official not voting), or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAAA, and, the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. SCIENTIFIC BACKGROUND AND RATIONALE OF INIA Background Chronic exposure to alcohol results in several neuroadaptative phenomena, including tolerance, sensitization, dependence, withdrawal and relapse, that may contribute to the development of alcohol abuse and alcoholism. However, despite many years of study of the biochemistry, anatomy, and physiology of these neuroadaptive processes, the precise roles of these processes in mediating excessive alcohol intake is still unclear. An integrative approach that combines the use of animal behavioral models with molecular, cellular, and systems level measures of brain function will clarify these roles. Research on neuroadaptation related to chronic alcohol exposure falls into three general areas: behavior, neurobiology, and genetics. Behavioral Neuroadaptive Phenomena Tolerance. Tolerance, a diminished physiological or behavioral response to a particular dose of ethanol, can develop over the course of a single exposure (acute tolerance) or following repeated exposures (rapid and chronic tolerance). Most of the research on tolerance has focused on the physical measures (motor, hypothermic, sedative effects). However, more recently, theorists have highlighted the motivational aspects of tolerance, linking tolerance and withdrawal as components of the same neuroadaptive process. The opponent-process theory posits that homeostatic adaptive processes counteract the initial acute effects of the drug. Removal of the drug unmasks this counteractive process and can result in a withdrawal syndrome (negative affective state). However, there is also sufficient evidence that alcohol tolerance depends on the learning process. Classically conditioned environmental cues or operant conditioning paradigms may produce internal adaptive responses that attenuate the effects of alcohol. On the other hand, tolerance can develop in novel environments where conditioning effects are minimal. The neural circuitry and neurobiological mechanisms that distinguish the temporal, physiological, motivational, and learning components of tolerance are currently unknown. An important question is whether a causal link exists between tolerance and the development of alcohol dependence. Some evidence suggests that tolerance to the aversive effects of alcohol unmasks ethanol"s hedonic effects and may increase drinking. Another mechanism suggests increased intake results from tolerance to alcohol"s reinforcing effects. Changes in the brain reward system have been implicated, but the exact mechanisms mediating tolerance to alcohol’s rewarding effects remain to be demonstrated. Using selectively bred animals, alcohol-preferring rats show more behavioral tolerance to alcohol than do alcohol-nonpreferring rats. Tolerance to ethanol-induced ataxia and hypothermia correlate with initial sensitivity in C57BL/6J and DBA/2J mice and their recombinant inbred strains. Although correlational studies can generate hypotheses about common genetic mechanisms, targeted mutagenesis may provide a more powerful tool for demonstrating a causal link between tolerance and dependence. Sensitization. Behavioral sensitization, a process by which the response to a drug increases with repeated exposures, suggests that repeated use of a drug increases its incentive value, leading to increased use. Environmental cues and stressors can contribute to the development of drug sensitization. Much of the work on sensitization derives from studies on enhanced locomotor activity produced by psychomotor stimulants. Although sensitization to the activating effects of low to moderate doses of ethanol has been demonstrated, as well as elevated sensitivity to ethanol"s effect on brain stimulation reward, ethanol sensitization has not been consistently reproduced in animals because of species and strain differences. Another type of ethanol sensitization is the increased withdrawal response following multiple intoxication and withdrawal episodes. Progressive intensification of withdrawal seizures following repeated alcohol withdrawal episodes has been demonstrated in mice and rats, and is referred to as "kindling" because of its similarity to kindled brain seizures. Research is needed to elucidate the neural mechanisms and circuits as well as genetic and environmental factors that contribute to ethanol sensitization and its relationship to alcohol dependence. Dependence, Withdrawal, and Relapse. Abrupt discontinuation of chronic alcohol consumption often results in a withdrawal syndrome. These symptoms include autonomic hyperactivity, tremors, seizures, perceptual distortions, and affective changes. Investigators have more recently concentrated on neural circuits related to the negative affective component of withdrawal (e.g., anxiety, stress, depression, and insomnia). These studies suggest that alcoholism is maintained, in part, by a need to reduce the negative emotional states associated with abstinence and withdrawal. Because brain stimulation reward techniques reveal a prolonged increase in reward thresholds following chronic alcohol administration, brain reward circuits (i.e., the median forebrain bundle) may be disrupted by chronic alcohol administration. A key area for research is to understand neuroadaptive factors that contribute to relapse. Animal models are available to study the neurobiological mechanisms by which repeated cycles of excessive drinking and withdrawal increase the likelihood of relapse. One model, which emphasizes enhanced reinforcing properties as a mechanism of relapse, is the alcohol deprivation effect, a transient increase in alcohol consumption following periods of forced abstinence. In lines of alcohol-preferring rats, repeated deprivation cycles and extended deprivation periods (2-8 weeks) prolonged the deprivation effect and enhanced the reinforcing efficacy of ethanol. Another recent model, based on the concept of allostasis, focuses on negative emotional factors during withdrawal as the basis for drug relapse. Allostasis is a change in the internal set point of a physiological regulatory system outside the normal range. By decreasing brain reward function during withdrawal (due to negative symptoms), chronic alcohol use causes an allostatic elevation of the ethanol reward set point or threshold. These alterations could explain alcohol relapse and increased intake as a means to reinstate normal reward function and to achieve the same rewarding effects previously experienced with ethanol. Recent studies in rats indicate that experience with alcohol can induce long lasting changes in the reinstatement of alcohol use after protracted abstinence. These approaches can be used to study the underlying cellular, molecular, genetic and environmental mechanisms that lead to relapse. Currently, the biological mechanisms underlying the behavioral manifestations of neuroadaptation are not well understood. In addition, the relevance of these phenomena to excessive ethanol intake has not been elucidated. More research is needed to clarify causal relationships between behavioral adaptive responses and neurobiological adaptive responses. Biological Neuroadaptive Phenomena Molecular, Cellular & Anatomical Neuroadaptation. The behavioral neuroadaptive phenomena discussed above are long lasting, are independent of the presence of ethanol, and are believed to result from neuroadaptive changes in the brain. When perturbed, the brain attempts to maintain homeostasis in several ways. The most immediate compensatory changes occur in the synthesis and release of neurotransmitters. This is accomplished by feedback to enzymes that synthesize them or by altering the activity of presynaptic autoreceptors, thereby altering the rate of neurotransmitter release. In most cases, this mechanism, initiated over minutes to hours, is sufficient to maintain neural activity within a physiological acceptable range. If the perturbation is removed early, systems quickly revert to their basal levels. Over a period of hours to days, other changes with longer lasting effects occur. These changes include up- and down-regulation of receptors or ion channels, alterations in signal transduction pathways, and changes in gene expression. Post-synaptic up- and down-regulation of receptors and ion channels occurs in response to chronic changes in synaptic input. This can involve changes in the synthesis of the receptor or one or more of its subunits to compensate for the altered synaptic input. For example, if synaptic input is impaired, synthesis of postsynaptic receptors increases. Studies of other acquired long-term changes in brain function can provide a paradigm for studies of the effects of chronic ethanol exposure. For example, the downstream consequences of learning are both morphological and molecular. Synaptogenesis as well as pruning of synapses and changes in shape and number of dendritic spines have been known for some time. It is of interest that such morphological changes have been observed in cortex of rats sensitized to cocaine and it seems likely that alcohol dependence also produces such changes. In addition, learning also remodels individual synapses at the molecular level with changes in receptor density, receptor types and activity of protein kinases and phosphatases as has been observed with chronic alcohol exposure and discussed previously. Of particular note is the insertion of AMPA receptors into the postsynaptic membrane during LTP. Recent evidence suggests that the acquisition of a new behavior, such as increased alcohol consumption, may rely on some of the same changes in neurocircuitry as are found in learning and memory. Thus, better understanding of mechanisms of neuroadaptation to alcohol may result from research on changes in molecular circuitry defined in models of learning such as LTP and LTD as well as more complex paradigms. Post-translational modification of proteins can occur in response to abnormal neural activity in an attempt to maintain normal synaptic function. There are several mechanisms by which protein modification can occur in response to altered synaptic function. For example, protein kinases, which catalyze the phosphorylation of specific substrate proteins, are activated by a variety of intracellular messengers, including cyclic nucleotides, calcium, nitric oxide and the metabolites of phosphatidylinositol and arachidonic acid. There is the potential for an alcohol perturbation to differentially affect the many protein kinases. Because kinases have different protein substrates, different amounts of alcohol can lead to different degrees of altered synaptic function. It is important to understand the differential effects of alcohol at the molecular level to understand the behavioral adaptation to alcohol intoxication. Investigators have characterized a multitude of changes in gene expression induced by chronic ethanol exposure in brain and in cultured neurons, including transcription factors, signal transduction components, and neurotransmitter receptors. The behavioral significance of the vast majority of these changes is still unclear. For example, the catalytic subunit of PKA in NG108-15 cells exposed to ethanol translocates to the nucleus where it phosphorylates CREB. It seems reasonable to presume that a similar translocation would occur in neurons in the brains of mice (or humans) exposed to ethanol. Phosphorylation of CREB would be expected to lead to widespread changes in gene expression. However, because of the many other molecular changes induced by ethanol (independently of its effects on PKA), it would be impossible to determine from measurements of gene expression alone which changes actually mediate ethanol-induced changes in behavior. The use of gene knockouts in mice has begun to clarify this confusing picture. Mice lacking the gene encoding a regulatory subunit of PKA show increased consumption of ethanol, and reduced sensitivity to its sedating effects, thereby implicating PKA in the regulation of these behaviors. NIAAA therefore strongly encourages Investigators to use mouse gene knockouts (and more sophisticated modifications of this methodology) to elucidate causal relationships between gene expression and behavior. Identification & Characterization of Neural Circuits. Identification and characterization of neural circuits in the brain that mediate the myriad of neuroadaptive behavioral effects of chronic ethanol exposure is another important objective of alcohol research. As discussed previously, the actions of alcohol on the brain have been intensively studied at both the molecular and behavioral levels. These studies have provided abundant information on the potential molecular targets of ethanol and on candidate neural pathways involved in its behavioral effects. To bridge the gaps between these molecular and behavioral studies, further research at the neural circuit level is crucial and can now be pursued applying several recent technical advances, which should facilitate finding the neural circuits underlying neuroadaptative responses to alcohol exposure. An important part of this initiative is the study of the circuit as a whole rather than focusing on a specific nucleus or brain area. Neural circuits have been studied for the acute reinforcing effects of ethanol. A loop that starts in the ventral tegmental area appears to mediate reward of a variety of substances and stimuli, including ethanol and most other addictive drugs. Neurons originating from this region project to the nucleus accumbens, and ultimately to the prefrontal cortex. Completing the circuit, neurons from the nucleus accumbens and the cortex project back to the ventral tegmental area. The actions of ethanol on parts of this circuit have been extensively studied such as on the ventral tegmental area and the nucleus accumbens, whereas the prefrontal cortex and its connections to the ventral tegmental area have received less attention. In addition, the amygdala as well as the hippocampus may be part of the circuit or regulate it because of their role in associative learning, a process required to associate drinking alcohol and obtaining a positive response. However, it is not clear how this reinforcing circuitry contributes to excessive ethanol consumption. Similarly, other circuits may mediate other actions of ethanol such as sedation and aggression, as well as the manifestations of ethanol dependence. Motor dysfunction has been shown to involve the cerebellum and basal ganglia. Various known neural circuits may be involved. For example, in the cerebellum, cerebral input through the inferior olivary nucleus in the brain stem to Purkinje cells in the cerebellum back to the cerebral cortex is one possibility. In the basal ganglia, a neural circuit involving a loop from the substantia nigra to the caudate nucleus and back, with input from the cerebral cortex, putamen and globus pallidus, is another option. Again, how these circuits might contribute to behavioral neuroadaptive phenomena has not been addressed. Molecular studies indicate that ethanol can interact with many major central neurotransmitter receptors, including those for GABA, glutamate, dopamine, serotonin, acetylcholine, and some peptide neurotransmitters. Imaging, behavioral, and neuropharmacological studies have begun to reveal candidate brain regions that are involved in different ethanol-associated behaviors. These studies have helped identify possible circuits based on known anatomical connections. To understand the mode of operation of a given neural network, the different neurons that form the circuitry should be identified, their membrane properties should be defined in terms of their firing properties, and a description should be made of how these neurons interact synaptically in both spatial and temporal terms. To accomplish this, newly developed techniques will allow simultaneous in vivo measurements of electrical and chemical responses to ethanol from groups of individual neurons in more than one brain region during ongoing behaviors. Other approaches will permit in vitro recordings from up to hundreds of neurons connected by different neural pathways. Extracellular, single-unit recordings in anesthetized animals have long been used in neurophysiological studies. Recently, modified methods of single- unit recordings in freely behaving animals have converted this classic technique to a powerful new tool to study ethanol-induced impairments in motor and cognitive behaviors. Another newly developed technique, the multi- electrode single-unit recording in freely behaving animals, is even more powerful in neural circuit studies, especially when applied to neuropharmacologically defined neurons. With this sophisticated approach, patterns of electrical activity of individual neurons from different areas of a distinct neural circuit can be measured simultaneously during a specific behavioral event. This method also will allow analysis of changes in spatiotemporal patterns of neuronal activity related to ethanol-associated behaviors. Neurochemically, in vivo microdialysis, iontophoresis, or fast-scan cyclic voltammetry, when combined with electrophysiological and behavioral approaches, provide a means of simultaneously recording neurophysiological and neurochemical activities in real-time with ongoing behaviors. Recent research has demonstrated that microdialysis probes can be used in more than one brain area at the same time. Coupled with local delivery of ethanol and neurotransmitter receptor agonists or antagonists to individual neurons or brain regions, transmitter release can be related to ethanol-induced events from the same neurons or regions in freely behaving animals. At the cellular level, various sophisticated optical methods including confocal microscopy, semiconductor array imaging, two-photon laser scanning microscopy, nonlinear fluorescence imaging, and fluorescent indicators of ion concentration and transmembrane electrical potential have been developed in the past decade. Unlike classical electrophysiological methods, optical recordings can assess the activities of a large number of neurons from different parts of a circuit simultaneously, as well as both structural and functional changes induced by ethanol. Although most of the optical recording methods can be used only in vitro, some of them also can be used in living tissues such as the newly developed organotypic brain slice and transplant. Some optical techniques can even be applied in vivo. These cutting-edge approaches have shown great promise in studying neural circuits. Once they are introduced and incorporated into alcohol research, more mechanistic questions of neural circuits mediating ethanol-related brain dysfunction can be addressed from several different levels. Many if not most actions within the brain are under genetic control. In the case of neural circuits, genes not only regulate the production of the structure of neural circuits, they also regulate the expression of behavior mediated by those circuits. The proteins involved can include enzymes mediating the synthesis and degradation of neurotransmitters, their receptors, and various postsynaptic signal transduction pathways. Examining changes in genetic expression underlying changes in alcohol-modified neural circuits that accompany and presumably cause, the acquisition of excessive alcohol consumption are important areas of research. It should be noted that changes in gene expression must also be used to focus studies on changes in functional proteins as well as neuronal morphology. Thus, examination of molecular, anatomical and electrical circuitry must proceed together and inform each other of the most pertinent targets for analysis. Genetic Models of Neuroadaptation Innovative Animal Models of Alcohol-Related Phenomena. Development of appropriate and well-characterized animal models of alcohol-related phenomena is necessary for successful integration of neuroscience research. Animal models already developed for specific alcohol-related phenomena include invertebrates, rodents, and non-human primates, with different models being selected on the basis of specific research questions being asked. Given that each organism and each model has strengths and weaknesses, there is no single optimal model for any research question. Therefore, a continued investment in the development of models of alcohol-related phenomena is required for successful integration of neuroscience information. Examples of some possible models are described to highlight particular strengths. A readily manipulated and relatively inexpensive species for gene identification is the fruit fly (Drosophila melanogaster). This species has already been used to link a specific gene with increased sensitivity to the acute effects of alcohol. Studies with Drosophila, as well as C. elegans (whose genome has been recently published) have the potential of rapidly identifying genes underlying an alcohol-induced behavioral trait. Because so many genes are conserved through evolution, the genes and proteins identified can give significant clues for future study in mammals. Inbred mice and rats have been used successfully to identify chromosomal regions containing genes (Quantitative Trait Loci -- QTLs) influencing alcohol-related phenomena, and studies are underway to identify these genes. The completion of the mouse and rat genome sequences will accelerate the pace of these studies. QTL mapping studies have led to the generation of numerous strains congenic for small genomic regions bearing alternate alleles of genes influencing various kinds of ethanol-related behavior. Congenic strains differing at a relatively small number of genes (compared to the number differing between two selectively bred lines) can be used to discover genetic correlations between physiological and behavioral traits. Thus, correlated physiological and behavioral traits observed in congenic strains have a correspondingly greater likelihood of being influenced by the same gene, and hence mechanistically related to each other. Comparisons between the physiology and behavior of congenic strains thus provide a firmer basis for inference of physiological mechanisms of behavior than perhaps comparisons between selectively bred lines. The ability to create mice and rats with defined genetic alterations will be critical for establishing the role of specific proteins in mediating specific behavioral endpoints of neuroadaptation to alcohol. Directed mutagenesis and overexpression will complement traditional pharmacological approaches to perturb protein function. These methods are particularly useful in situations where ligands for a protein of interest are unavailable, or where available ligands are not sufficiently specific to differentiate the functions of closely related proteins. Directed mutagenesis will also prove essential to identify QTL alleles responsible for natural inter-individual variation in neuroadaptive responses. In addition, it will provide a critical means of demonstrating an obligatory role in neuroadaptation for the products of genes whose expression changes during this process. The capability of creating mice with defined genetic alterations serves an integrative function by permitting exploration of both the physiological and the behavioral consequences of altering the activity of a specific protein. High-Throughput Gene Expression Assays (cDNA and Oligonucleotide Microarrays) Long-term changes in the physiological properties of neurons and the circuits in which they function are often mediated by changes in expression of genes encoding neuronal components (e.g., receptors, ion channels, intracellular signaling apparatus, cell adhesion molecules). While alcohol researchers have begun to characterize alcohol-induced changes in expression of genes encoding some of the better characterized receptors (e.g., GABA, NMDA), these studies are in their infancy. The imminent identification of all the genes in the human and murine genomes suggests the possibility of much more comprehensive studies of changes in gene expression of neuroadaptation to alcohol, examining changes in the expression of tens of thousands, rather than merely tens, of genes. Such studies promise to yield a clearer picture of which neurochemical pathways change their activity during adaptation to alcohol. These studies serve an integrative function by virtue of their ability to examine changes in gene expression at levels of resolution ranging from brain-regional to cellular. Additional Technological Approaches Development of Imaging Technolgy for Animal Models. Most noninvasive functional imaging studies to date in humans and animals have investigated the acute and chronic effects of alcohol on local cerebral metabolism or regional cerebral blood flow to establish detailed neuroanatomical patterns of changes in functional activity throughout the brain. To study the neuroadaptive changes associated with chronic alcohol use, longitudinal studies following chronic ingestion are needed to distinguish withdrawal- related changes in brain metabolism from irreversible changes, and to determine the effects of abstinence on recovery of brain metabolic function. Integration of behavioral measures with these imaging studies could reveal neural circuits associated with alcohol-related neuroadaptive phenomena. Functional imaging technologies have the most promise for alcohol research in bridging the gap between brain chemistry and behavior. Magnetic Resonance (MR) imaging is also an important modality for noninvasive functional imaging animal studies of acute and chronic alcohol effects. Structural MR can be used for highly detailed tracking of brain tissue loss and recovery over the course of alcohol exposure and withdrawal. Furthermore, MR spectroscopy can provide information about the integrity of neuronal tissue with the determination of brain tissue concentrations of the neuronal marker, N- acetyl-aspartate (NAA) and the presence of gliosis with determination of concentrations of myo-inositol (mI). MR spectrocopy can also be used to determine the brain concentration of alcohol in vivo and MR spectroscopy can be employed in both single voxel and imaging modalities, the latter providing information about the spatial distribution of certain metabolites. Although some amine and polypeptide receptor ligands have been labeled with radiotracers, only a few studies using positron emission tomography (PET) have measured alcohol"s effects on neurotransmission. Furthermore, because alcohol affects many neurotransmitter systems, the development of new ligands targeting the glutamate, cholinergic and serotonin receptors are needed to combine functional imaging, neurochemistry, and behavior to eventually understand the underlying mechanisms of neuroadaptive changes, such as sensitization, tolerance, dependence, and withdrawal. Thus, the development of imaging technologies for animals including rodents and primates could provide important information. Rodent animal models can be used for initial ligand development and testing and will be informative for determining responses that are specific to alcohol exposure. So far, functional imaging studies utilizing glucose metabolism in rodents have not allowed repeated testing in the same animal. Development of small animal imaging techniques would be more amenable to studying neuroadaptive changes in the same animal. In addition, rodent imaging would allow integration of genetic and imaging techniques. For example, genetically engineered rodent models have been used in alcohol research to study both pharmacological as well as behavioral processes. Consequently, there are distinct advantages to studying alcohol- related phenomena in the rodent where imaging and genetic techniques can be used in the same animal. Computational Neurobiology and Informatics. Computational neurobiology integrates the disciplines of neurobiology, mathematics, and physics to study the functional organization and operation of the brain. Neural networks mediating alcohol-related phenomena are hypothesized or empirically established and then modeled to determine, in an iterative process, the organizational principles and mechanisms underlying the targeted phenomena. It is anticipated that distributed neural networks are involved and are organized by coupled dynamic rules. Computational neurobiology has been used successfully in systems-level models and in integrative approaches that incorporate data from the subcellular to behavioral levels. Databases need to be developed to provide, in a user-friendly format, research information that is collected by individual investigators of INIA. Access by all investigators to genetic, molecular, cellular, anatomic, physiologic, neural network, and behavioral data is required to perform successful integrative neuroscience research. Moreover, new methods are needed to facilitate the extraction of information from these large databases. STUDY POPULATIONS 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 new 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 (, a complete copy of the updated Guidelines are available at 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: Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT The consortium coordinator should submit a letter of intent that includes 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 applications are being 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Extramural Project Review Branch Office of Scientific Affairs, NIAAA 6000 Executive Boulevard, Suite 409 Bethesda, MD 20892-5452 (for express/courier service: Rockville, MD 20852) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES All applications for an INIA Consortium will be compiled and submitted by the consortium coordinator. It will include the Consortium Coordinator’s application as the lead application (described previously in more detail under Organization), the individual research project component applications as well as the resource core applications. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards, with the modified format that is described below. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: For each research project or core component of the consortium, a signed, typewritten original application, five exact single-sided copies, and five sets of appendix material must be submitted as specified under APPLICATION SUBMISSION below. Each application must be complete, with all approvals, budgets, and signatures from the appropriate officials of the applicant institution. All of the U01 and U24 applications constituting the proposed consortium must be submitted in a single package by the consortium coordinator. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. The sample RFA label available at: has been modified to allow for this change. Please note this is in pdf format. Cover Letter: A cover letter that identifies the total number of applications in the consortium and the principal investigator for each Research Project Component and Resource Core must be enclosed in the package of applications by the consortium coordinator. For each component application in the consortium, the original, five copies, and the appendix material must be bundled together, clearly identified, and submitted as specified under APPLICATION SUBMISSION below. Failure to follow the instructions regarding application receipt dates and packaging may lead to a delay in review. Each application must have its own descriptive title and a principal investigator. The contributions from Resource Cores must be summarized in item (i) CONSULTANTS of the Research Plan. This must include an explicit description of the methods and procedures to be used, the services, tests, animals, or facilities to be provided, and a description of the involvement and protection of human subjects or vertebrate animals, if appropriate. This section should also describe the collaborative and integrative interactions of the project with other projects of the consortium. Item (i) must be complete, with enough detail for NIH staff and reviewers to understand the full scope of these interactions. Instructions for Preparing Applications on the PHS 398 (rev. 4/98) The following instructions address ONLY the parts of the PHS 398 research grant application form for which information about the proposed interactive research consortium is requested. All other parts of the grant application should be prepared according to the instructions in the PHS 398 booklet (rev. 4/98). FACE PAGE - AA: Item 2. Mark "Yes" and enter the RFA announcement number and title. Items 7-8. Enter the direct costs and total costs - includes the costs of the specific research project. Form BB: Description. Provide a brief description (abstract) of the research proposed according to the instructions provided on page 10 of booklet for the PHS 398 (rev. 4/98). The description of the proposed interactions with the Consortium and the contribution of any of the Resource Cores to this application may be included. Performance Site(s). The performance site(s) of THIS project AND of any Resource Core in the consortium that will be used in this project (any involved institution should be named only once). Key Personnel. List first the principal investigator and key personnel engaged on THIS project, followed by all key personnel engaged on any Resource Core that supports this project. Then list, as collaborators, all principal investigators and professional personnel engaged in other research component projects of the consortium that interact specifically with this project application. Form CC: TABLE OF CONTENTS. Add the page locations for item (i) of the Research Plan and for each of the shared resource cores proposed to be supported through this application. Forms DD and EE: Project Budget. Complete these pages as directed with the budget requests for this research project only. Provide clear justification for all items requested in the first year and for any significant increases or decreases in any category in future years. Form FF: The biographical sketch for each key investigator involved and to be supported in this project should be included. RESEARCH PLAN: The instructions in section C-9 (pages 14-19) of the PHS 398 must be followed to complete a. through d. (Page 16) of the Research Plan in detail. Attention may be given to the integration of the individual project into the overall consortium effort. The overall research plan (a-d) for the project may not exceed 25 pages. The following points may be addressed in the appropriate sections. a. SPECIFIC AIMS. Besides listing the specific objectives of the individual research project for the total period of requested support, briefly summarize how the overall objective or long-term goal of the research relates to the goals of the consortium. b. BACKGROUND AND SIGNIFICANCE. Besides discussing the overall scientific significance of the proposed research, this section may briefly summarize the relevance of the project to the scientific goals of the consortium. APPLICATION SUBMISSION 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 20827 (for express/courier service) At the time of submission, two additional copies of the application plus all five sets of the appendices must also be sent to: Chief, Extramural Project Review Branch Office of Scientific Affairs, NIAAA 6000 Executive Boulevard, Suite 409 Bethesda, MD 20892-5452 (for express/courier service: Rockville, MD 20852) Telephone: (301) 443-4375 FAX: (301) 443-6077 Applications must be received by April 27, 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 announcement 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, each cluster of applications will be reviewed for completeness by the Center for Scientific review (CSR) and for responsiveness by the NIAAA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NIAAA in accordance with the review criteria stated below. As part of the initial scientific 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, assigned a priority score, and receive a second level review by the National Advisory Council on Alcohol Abuse and Alcoholism. Review Criteria for the Consortium Coordinator Application (lead application and overall consortium) The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed multidisciplinary initiative will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. 1. Significance: Does this interactive multidisciplinary consortium project address a complex biological problem of overarching significance to biomedical science that would be difficult to address by separate grants? If the aims of the overall consortium are achieved, how will the scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Do the arrangements for data sharing maximize the impact of the interactive consortium project? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the scientific aims of the collaborative project? Does the applicant acknowledge potential problem areas and consider alternative tactics or designs? Is the project management plan adequate? Is the administrative framework appropriate? Do milestones articulate key indicators set for appropriate times that will demonstrate significant forward progress for the consortium project? Are the plans to monitor and evaluate progress of the consortium project adequate? Are the plans to share the data and findings within the consortium and the larger scientific community adequate? 3. Innovation: Does the project employ novel concepts, approaches, theories, or methods? Are the aims original and innovative? Will the multidisciplinary collaborative consortium challenge existing paradigms or develop new methodologies or technologies? Will the multidisciplinary consortium attack a problem in a significantly new way? 4. Investigators: Is the consortium coordinator’s major research activity within the research area of the multidisciplinary consortium? Is the consortium coordinator well suited to the scientific and administrative leadership required to carry out this work? Is the level of effort proposed for the consortium coordinator appropriate? Is the work proposed appropriate to the experience level of the multidisciplinary consortium’s research and technical staff? Are the research project component applications of the participating investigators within the area of the multidisciplinary consortium? Are the participating investigators well chosen for their roles in the collaborative project? 5. Environment. Do the scientific environments in which the work will be done contribute to the probability of success? Are support personnel and resources in place to advance the work? Will the proposed multidisciplinary consortium take advantage of unique features of the scientific environments of the component projects? Is there evidence of institutional support? Are the requested core facilities critical to achieving the scientific goals of the multidisciplinary consortium, are they cost effective? Is access to the core facilities appropriate? 6. Budget: Is the requested budget and estimation of time to completion of the study appropriate for the proposed research? In accordance with NIH policy, all applications will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children, as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Review Criteria for Core Resources Consideration of the technical merit of the core units will include: (1) Facilities within the resource cores compared to the state-of-the-art. The contributions of the resource cores to fulfilling the goals of the consortium. (2) The adequacy of the approaches, methods and operational procedures for interacting with the consortium investigators. (3) The extent to which resource core units promote greater collaboration and cohesiveness among the participating investigators. (4) Qualifications, experience, and commitment to the INIA mission of the investigators responsible for the core resources and their abilities to devote the required time and effort to the program. (5) Appropriateness of the budgetary requests. Review Criteria for Research Project Components: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of each research project application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of the criteria listed below will be addressed and considered in assigning the score for a research project, weighting them as appropriate for each project. Note that the project does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. In their evaluations, reviewers will comment on: (1) 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 achieving the goals of the collaborative projects or consortium? Will the project tie or enhance the independent work of the participating investigator to the collaborative project, or will the project add an essential missing aspect to the collaborative project? (2) Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) 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? (4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all individual scientific projects will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. The scientific review group will also examine the provisions for the protection of human subjects and the safety of the research environment. Schedule Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: April 27, 2001 Peer Review Date: July, 2001 Council Review: September 19, 2001 Earliest Anticipated Start Date: September 28, 2001 AWARD CRITERIA Award 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Antonio Noronha, Ph.D. Chief, Neurosciences & Behavioral Research Branch Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 301-443-7722 (office) 301-594-0673 (fax) Email: Direct inquiries regarding fiscal matters to: Ms. Linda Hilley Chief, Grants Management Office Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 504 6000 Executive Boulevard, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 FAX: (301) 443-3891 Email: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all award recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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