RFA-AA-02-004: NEW APPROACHES TO DEVELOPING PHARMACOTHERAPY FOR ALCOHOLISM

Department of Health
and Human Services (HHS)

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NEW APPROACHES TO DEVELOPING PHARMACOTHERAPY FOR ALCOHOLISM Release Date: September 27, 2001 RFA: RFA-AA-02-004 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov/) Letter of Intent Receipt Date: December 28, 2001 Application Receipt Date: January 23, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites applications for grants proposing innovative basic research for the development of pharmacotherapeutic agents for alcoholism, alcohol abuse, and alcohol-related medical consequences. Alcohol researchers have made significant strides in uncovering mechanisms of action and developing experimental models of alcoholism, alcohol abuse and associated problems. Although much of this work has potential implications for pharmacotherapy, studies are often not designed to support future therapeutic possibilities. To facilitate discovery of compounds having possible therapeutic efficacy we are requesting grant applications proposing research which: (1) elucidates the mechanisms of action of drugs currently believed to be effective in treating facets of alcohol abuse and those having effects suggestive of a therapeutic effect in animal and human experimental paradigms, (2) identifies candidate molecular targets and promising therapeutic compounds based on current knowledge of alcohol’s molecular, physiological and behavioral mechanisms of action, or based on current understanding of the etiology of alcohol related disease, or based on using functional genomics and proteomics to identify compounds with possible therapeutic value, (3) develops animal and human laboratory models having high predictive validity for clinical problems associated with alcohol abuse with emphasis on rapid testing. Proposed research may encompass any stage of the medications development process from chemical synthesis, genomics, proteomics, in vitro pharmacological studies, and in vivo pharmacokinetic, toxicity and bioavailability assessment, to behavioral and physiological studies in rodents, non-human primates and humans. Proposals may be hypothesis driven basic research studies emphasizing a particular stage in the medications development process, but must contain a component which clearly establishes relevance to other stages in the process. Results from these studies will lead to integrated efforts toward developing medications for alcoholism and alcohol abuse. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), New Approaches to Developing Pharmacotherapy for Alcoholism, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01), exploratory/developmental grant (R21), and small grant (R03)award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Applicants for R01s may request support for up to 5 years. Currently, small grants (R03) are limited to 2 years for up to $50,000 per year for direct costs, and exploratory/developmental grants (R21) are limited to $100,000 per year for direct costs for up to 3 years. Exploratory/developmental grants and small grants cannot be renewed, but grantees may apply for R01 support to continue research on the same topics. Applicants may also submit applications for Investigator-Initiated Interactive Research Project Grants (IRPG). Interactive Research Project Grants require the coordinated submission of related research project grants (R01) from investigators who wish to collaborate on research, but do not require extensive shared physical resources. These applications must share a common theme and describe the objectives and scientific importance of the interchange of, for example, ideas, data, and materials among the collaborating investigators. A minimum of two independent investigators with related research objectives may submit concurrent, collaborative, cross- referenced individual R01 applications. Applicants may be from one or several institutions. Further information on these and other grant mechanisms may be obtained from the program staff listed in the INQUIRIES section of this RFA or from the NIAAA Web site http://www.niaaa.nih.gov/. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2002. FUNDS AVAILABLE NIAAA intends to commit approximately $2 million in FY 2002 to fund approximately 6 to 10 new and/or competitive continuation grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Although medications are commonly used to treat alcohol withdrawal, their use in treating other facets of alcoholism remains limited. This is due, in part, to a limited arsenal of effective pharmacotherapy. Since 1949, only disulfiram and naltrexone have been approved in the United States for reducing alcohol drinking in alcoholics. Identifying compounds having potential therapeutic efficacy for alcohol related problems can be promoted through a variety of basic research tactics such as elucidating the mechanisms of drugs already having demonstrated clinical efficacy, and using knowledge of neuronal pathways mediating alcohol drinking in experimental models to develop compounds acting on specific molecular and cellular targets. Prototypes might also come from existing libraries of compounds or may be novel compounds developed based on rational molecular design using knowledge of receptor structures and ion channels involved in alcohol"s actions on the nervous system and other organ systems. Evaluating the effects of compounds having potential clinical value in experimental models using animal and human subjects is essential in the early stages of medications development, and depends on the predictive validity of the experimental models. Therefore, developing effective experimental models for conditions associated with alcoholism and alcohol abuse is also important. Expanding on Current Pharmacotherapy for Alcohol Drinking. Current pharmacotherapy seeks to deter drinking by making the effects of alcohol ingestion aversive, or else to directly reduce alcohol consumption or craving by inhibiting the reinforcing effects of alcohol. The dysphoric reaction which occurs when alcohol is ingested after taking the aldehyde dehydrogenase (ALDH) inhibitor disulfiram is believed to deter subsequent drinking in some alcoholics. Disulfiram’s efficacy may be impeded by aversive side effects and the extensive process of bioactivation required to produce adequate ALDH inhibition, particularly in those having liver damage. Nevertheless, evidence that an inactive ALDH allele may protect against developing alcohol abuse and alcoholism justifies further research on compounds which inhibit ALDH. Studies suggest the opioid antagonist naltrexone reduces alcohol euphoria, craving, and relapse in human alcoholics, but whether naltrexone’s therapeutic efficacy is entirely mediated by blocking alcohol’s effects on the endogenous opioid system remains an open question. Naltrexone reduces a variety of positively reinforced ingestive and non-ingestive behaviors in laboratory studies which suggests naltrexone’s effects may not be specific to alcohol. The homotaurine derivative acamprosate has performed successfully in clinical trials, and reduces alcohol drinking in animal models, but its precise mechanism of action remains unclear. Earlier studies suggested acamprosate interacts with GABA receptor function. Recent studies suggest acamprosate interacts with NMDA receptor mediated glutamatergic transmission in cortical brain regions, although this conclusion has been questioned. Basic research clarifying the mechanism of known effective compounds will lead to identifying additional agents having similar action which can then be assessed for effects on alcohol related characteristics. Identifying New Therapeutic Compounds A spectrum of neurotransmitter systems (e.g., GABA, NMDA, 5-HT, dopamine), neuropeptide systems (neuropeptide Y, leptin), signal transduction pathways (PKA, PKC), and gene transcription factors (delta fosB) have been implicated in alcohol dependence and craving. New therapeutic compounds may emerge from further research on known ethanol targets, or may occur by identifying possible therapeutic targets and prototype drug candidates through research on systems and mechanisms not yet examined in relation to alcohol. As basic research reveals promising targets relevant to alcohol abuse and its consequences, analogs acquired from existing libraries, or newly-synthesized analogs developed through computational and combinatorial chemistry can be screened in vitro or in standardized behavioral assays for potential therapeutic efficacy. Another approach might be to target neurotransmitters and neuropeptides associated with neuronal circuits underlying alcohol dependence and craving or by directly counteracting the actions of alcohol at various ethanol- sensitive sites. Membrane proteins, including voltage-gated calcium channels and ligand-gated receptor/channel complexes (e.g., GABA, glycine, NMDA, 5-HT, nicotinic cholinergic receptors), have proven to be sensitive targets of alcohol action. Effects of alcohol on such proteins have been studied extensively, and analyzed with prototype agonists and antagonists. Receptor expression, distribution, post-translational modifications such as phosphorylation, and structural remodeling may account for acute sensitivity to alcohol as well as adaptive responses during long-term exposure, and present another possible target for therapeutic medications. Molecular and structure-function research approaches may define how ethanol interacts with membrane proteins and may support the feasibility of developing antagonists which directly block alcohol’s action on cell membranes. Initial studies suggest that certain amino acid residues on glycine and GABA receptors are especially important in determining how these proteins respond to ethanol. Related studies propose that ethanol inserts into hydrophobic pockets within the protein, or at the protein/lipid interface, thereby altering protein structure and functional interactions with receptor ligands. The long chain alcohol 1-octanol has been shown to abolish the detrimental effects of ethanol on cell-cell adhesion and consequent teratological damage by blocking ethanol action at one such site. Similar research on other types of receptors and channels may reveal a common set of interactions between alcohol and membrane proteins. Understanding these interactions will promote designing specific agents to counteract acute and chronic actions of alcohol. Likewise, molecular modeling will define the extent to which alcohol affects the structure and pharmacological properties of potential therapeutic agents. Signal transduction cascades and intracellular diffusible messengers mediate the effects of acute ethanol exposure and may participate in adaptive responses to chronic ethanol exposure. These systems exert widespread actions on cell metabolism and gene transcription, and they provide intricate pathways for feed-forward and feedback regulation of channels and receptors. Alcohol is known to affect PKA, PKC, Ca, PLC, and calcium-calmodulin kinase signaling systems. Phosphorylation of membrane proteins by appropriate kinases may account for time-dependent, model-specific, or tissue-specific differences in response to alcohol. PKC-epsilon activity has been reported to mediate up-regulation of N-type calcium channels in response to sustained alcohol exposure. Mice lacking PKC-epsilon display increased sensitivity to ethanol’s behavioral and biochemical effects, and reduced ethanol self- administration and handling induced withdrawal convulsions. Reduced cAMP-PKA signaling in mice engendered by targeted disruption of the Gs-alpha allele is associated with increased sensitivity the sedative effects of ethanol and decreased alcohol consumption. Mice lacking a regulatory subunit of PKA receptors are resistant to alcohol sedation and voluntarily consume more alcohol than normal mice. Further research suggesting ways to selectively modify PKC-epsilon and PKA signaling mechanisms pharmacologically may lead to medications which effectively reduce alcohol drinking in alcoholics. Lesser- known or more recently-discovered signaling systems (e.g., nitric oxide, endocannibinoids) also offer prime opportunities for medications development. Extending studies of signaling systems to periods of alcohol withdrawal and beyond may also prove fruitful. Further research on cellular structures and neuronal circuits having channels, receptors, and signaling systems with specialized functions relevant to alcohol action may reveal possible targets for medications development. Transmitter and receptor interactions in the ventral tegmental area and nucleus accumbens are of interest for their proposed role in alcohol reinforcement. Local circuits in cerebellum and hippocampus involve transmitters and modulators that also have demonstrated involvement in alcohol effects. Medications development in this context may address subtle aspects of intracellular communication and regulation, with resulting effects on particular facets of alcohol action such as ataxia, learning, memory, or reward. Advances in molecular genetics (e.g., microarray analysis, targeted mutations, proteomics) offer a powerful approach for broad-spectrum scanning of participants in the adaptive process. Individual gene clusters or functionally-related proteins can be identified in specific brain regions in temporal relation to alcohol exposure. Such studies may identify biochemical pathways and brain circuits which are preferentially recruited as alcohol dependence develops. Receptors or pathways involved in alcohol drinking and other alcohol effects can be disabled selectively with targeted knockout strategies. An unanswered question facing medical treatment concerns potential targets for modifying neurological changes underlying craving and alcohol-seeking after periods of prolonged abstinence. Developing Experimental Models Experimental research on pharmacotherapy for alcohol abuse and alcoholism rests on the quality of the experimental models. Research using animal subjects can address many facets of alcoholism including inherited predisposition, positive and negative reinforcing effects, subjective effects, relapse, and neuroadaptive consequences of exposure and abstinence. Well designed experiments can aid in developing drugs tailored toward specific facets of alcohol abuse. Non-human primate experiments may be especially desirable for research on pharmacotherapy for alcoholism. In addition to being genetically and physiologically more similar to humans, the longer lifespan of the monkey permits assessment of long term treatment efficacy, dose-effect manipulations, and assessment of combined pharmacotherapy. Using non-human primates also makes it possible to examine more complex behaviors (choice, cognition, social behavior) which may be directly relevant to the clinical situation. Extrapolating from animal studies to humans may be facilitated by studying multiple animals species (e.g., rodents and non-human primates), and by studying humans using comparable paradigms. Clinical trials would be justified when findings from preclinical human experiments are consistent with those from animal studies. There are many experimental models used in human laboratory studies which parallel those commonly used in animal studies of pharmacotherapeutic mechanisms (e.g., experimental alcohol self- administration and choice, ethanol discrimination training, laboratory measures of impulsivity, aggression, and cognition). Using these laboratory procedures to examine mechanisms underlying alcohol’s behavioral effects in humans will provide valuable information for planning clinical assessments. Although well developed behavioral models of clinical conditions are essential for preclinical studies, many require a great deal of time, and may not be ideal for screening compounds. Hence, it is desirable to develop rapid assessments which are strongly associated with facets of alcohol abuse as modeled in more extensive analyses. Such measures need not have apparent face validity as long as they have high predictive validity, and are relatively rapid and easy to conduct. Agents affecting alcohol responses in rapid assessment paradigms would be candidates for subsequent tests in more informative experiments which more directly reflect clinical situations. Alcohol Associated Dysfunction Research leading to effective pharmacotherapy for consequences of alcohol abuse (liver disease, birth defects, pancreatitis, hypertension, cardiomyopathy, and cognitive impairment) may incorporate many of the strategies discussed above. The possibility of protecting against alcohol- related birth defects and alcohol induced brain damage through pharmacotherapy is recent research showing that low doses of the long chain alcohol 1-octanol antagonizes ethanol inhibition of L1-mediated cell adhesion, and prevents subsequent dysmorphy and apoptotic cell death associated with alcohol exposure in mice. Prenatal administration of two active peptide fragments derived from ADNF to alcohol treated pregnant mice significantly increased the number of surviving fetuses and prevented reduced brain and body mass. Further research is needed to identify substances which protect against the destructive consequences alcohol exposure during development. Experimental models have been important tools in identifying brain damage and neurological dysfunction which is associated with a wide spectrum of cognitive disturbances associated with long-term alcohol exposure. Although laboratory learning tasks are widely available which are sensitive to effects of acute and chronic ethanol exposure, these paradigms have not been effectively used to test drugs which may improve cognitive function in alcoholics. Approaches to treating age related cognitive deficits and intellectual disabilities may be applicable. More research is needed to identify pharmaceutical interventions which can significantly reverse or protect against temporary and lasting cognitive impairment associated with alcohol ingestion. Examining transduction signal pathways involving neurotrophic factors and those leading to apoptosis as the brain reorganizes during prolonged alcohol exposure has potential for uncovering novel ways of counteracting alcohol-related neurotoxicity. A similar approach can be used to develop new treatments for alcohol-induced tissue injury. For example, advances have been made in understanding some of the factors contributing to alcoholic liver disease. Reactive oxygen species (ROS)resulting from alcohol metabolism have been shown to damage liver tissue. Increased and stable synthesis of the antioxidant superoxide dismutase (SOD) prevent ROS production and reduce injury due to oxidant stress. Intravenous administration of adenovirus containing the gene for SOD increases hepatic expression of SOD and reduces liver injury and pathology in rats. These findings raise the possibility using gene delivery to prevent and treat alcohol-induced liver injury. TNF-alpha levels in plasma and liver are elevated in humans and animals affected with alcoholic liver disease. In animal models of alcoholic liver disease, administering TNF-alpha antibodies attenuates liver injury and in TNF-alpha-receptor-1-deficient mice, chronic ethanol feeding fails to elicit liver injury. Thus, attenuation of TNF-alpha levels may help to ameliorate alcoholic liver disease in humans. Areas of Interest Applications may focus on any one of the five general Areas of Interest listed below. Proposals should include: (1) specification and rationale for the alcohol-related phenomena being targeted, (2) a theoretical basis and detailed methodology for laboratory studies, (3) a clear strategy for further advancing the development of promising compounds or therapies. Areas of research interest responsive to this announcement include, but are not limited to: (1) using knowledge of receptor structures, ion channels and cellular signal transduction mechanisms involved in alcohol"s actions on the nervous system to design new compounds (e.g., agonists, antagonists) for treating alcoholism and alcohol abuse (e.g., reducing the desire to drink, preventing withdrawal induced seizures). (2) using knowledge of the etiology of alcohol associated diseases to design new medications and treatments for medical conditions associated with alcohol abuse (e.g., fetal alcohol syndrome, liver disease, pancreatitis, cardiomyopathy). (3) testing the potential therapeutic efficacy of existing compounds having known pharmacological properties (e.g., GABA receptor antagonists, cannibinoid antagonists, CRF antagonists) in experimental models of alcohol associated problems. (4) developing new laboratory models with animal and human subjects having high predictive validity for specific clinical problems associated with alcohol abuse in humans (e.g., subjective states associated with craving, alcohol induced cognitive deficits). Emphasis will be on models that can be used for rapid testing. (5) conducting further basic research on the mechanisms of action of existing drugs and combinations of drugs currently believed to be effective in treating facets of alcohol abuse (e.g., naltrexone, acamprosate, SSRIs) or of drugs (e.g., isoflavones, CRF antagonists, CB1 antagonists, GABAa antagonists) demonstrated to have effects suggestive of a therapeutic effect (e.g., reducing alcohol consumption). This could lead to more specific treatment for alcoholics with specific combination of symptoms. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. DATA AND SAFETY MONITORING PLAN (applies if you have proposed a clinical trial): As of the October 2000 receipt date, applicants must supply a general description of the Data and Safety Monitoring Plan for ALL clinical trials, this must be included in the application http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html The degree of monitoring should be commensurate with risk. NIH Policy for Data and Safety Monitoring requires establishment of formal Data and Safety Monitoring Boards for multi-site clinical trials involving interventions that entail potential risk to the participants. The absence of this information will negatively affect your priority score. 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: RFA-AA-02-004 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. This version of the PHS 398 is available in an interactive, searchable PDF format. The NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Chief, Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and 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 merit review, all applications will 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application 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. (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 concepts or methods that drive this field? (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? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o 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. Schedule Letter of Intent Receipt Date: December 28, 2001 Application Receipt Date: January 23, 2002 Peer Review Date: March-April 2002 Council Review: May 2002 Earliest Anticipated Start Date: July 1, 2002 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 answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Mark Egli, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 [for express mail, use Rockville, MD 20852] Tel: (301) 594-6382 FAX: (301) 594-0673 Email: megli@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Judy Fox Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 505 6000 executive Blvd. (MSC-7003) Bethesda, MD 20892-7003 (For express mail use: Rockville, MD 20852) Telephone: (301) 443-2434 Email: jsimons@willco.niaaa.nih.gov 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 PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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