PEPTIDE REGULATION OF ALCOHOL INTAKE Release Date: August 23, 1999 PA NUMBER: PAS-99-156 National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: November 24, 1999 Application Receipt Date: December 22, 1999, standard receipt dates thereafter. THIS PROGRAM ANNOUNCEMENT (PA) USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites applications to identify peptides and their receptors that regulate alcohol consumption, ultimately leading to an understanding of their mechanism(s) of action. Although not exclusive, several areas have potential for further investigation including the hypothalamic-pituitary-adrenal axis, opioid peptides, the renin-angiotensin system, plus the group of peptides regulating food intake and energy balance, exemplified by leptin and neuropeptide Y. Evidence indicates that hormones regulating food intake (such as leptin and neuropeptide Y) may act upon the same neural circuitry in the brain that controls alcohol consumption. Therefore, studying the role of these peptides in the regulation of alcohol consumption is warranted. The goal of this initiative is to elucidate the role of peptides in pathological alcohol consumption, suggesting novel pharmacotherapeutic approaches for alcoholism. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led activity for setting priority areas. This PA, Peptide Regulation of Alcohol Intake, is related to the priority area of alcohol abuse and alcoholism. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. ELIGIBILITY 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 Research support may be obtained through applications for a research project grant (R01), exploratory/developmental grant (R21), and small grant (R03). Applicants for R01s may request support for up to 5 years. In FY 1998, the average total cost per year for new and competing renewal R01s funded by the Division of Basic Research was approximately $190,000. Currently, NIAAA Small Grants are limited to up to 2 years for up to $50,000 per year for direct costs and NIAAA Exploratory/Developmental Grants are limited to up to 3 years for up to $100,000 per year for direct costs. Applicants without extensive preliminary data are urged to submit applications for this PA using the exploratory/developmental and small grants mechanisms, and to use the preliminary findings obtained from the R03/R21 mechanisms to submit R01 applications under the regular application receipt dates. Exploratory/developmental grants and small grants cannot be renewed. Applicants who anticipate submitting a small grant or exploratory/developmental grant should contact the program staff listed under INQUIRIES or the NIAAA Home Page at http://www.niaaa.nih.gov for additional information on these mechanisms. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 PA or from the NIAAA Web site http://www.niaaa.nih.gov/. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE It is estimated that up to $2 million will be available to fund approximately 8-10 grants under this PA in FY 2000 and 2001. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit and availability of funds. The earliest possible award date is July 1, 2000. Future applications for regular research grant application receipt dates will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. RESEARCH OBJECTIVES Background Alcohol abuse and alcoholism afflict nearly 14 million Americans, resulting in more than 105,000 deaths annually, and the financial toll is approaching $167 billion in the United States this year. Nationwide, 20 40 percent of hospitalizations involve people being treated for complications related to drinking. Thus, understanding the reasons why some people drink to excess is an important goal of the NIAAA. Actions of alcohol on the brain, including the neuroendocrine system, are essential to understanding the mechanisms of alcohol abuse and alcoholism. Alcohol is a simple molecule with numerous actions on the body, particularly the brain. In addition to the classical neurotransmitters, many neuropeptides have been identified and are believed to act as modulators of neurotransmission. Although many actions of alcohol on neurotransmitters have been reported, the potential role of various peptides is not well understood. The most prominent peptides in alcohol research are the opioids because of the therapeutic use of naltrexone, an opioid antagonist, for treating alcoholism. Other peptides have not been extensively studied, including those with peripheral actions that might modify alcohol intake, such as the gut peptide cholecystokinin. Thus, examining the role of various peptides in the actions of alcohol presents an opportunity to explore new areas that may yield new approaches for treating alcoholism. RESEARCH AREAS OF INTEREST Based upon the information provided below, one has a diverse array of peptides and receptors, including some recently discovered molecules (e.g., the orexins) from which to study their individual and collective contributions to the regulation of alcohol consumption in humans and animals. Investigators are encouraged to explore their own lead candidates, or alternatively, pursue the discovery of new molecular entities. In either situation, research is encouraged to identify the following when relevant to the actions and/or consequences of alcohol use: the anatomical locations of peptides within the brain and in the periphery (if relevant), crucial neural pathways that mediate peptidergic effects, which peptides and/or other molecules are directly up- or down-regulated in the process, the role of peptide transport from the circulation to the CNS, and its potential perturbation by alcohol, and, at the cellular level, the characterization of peptide-receptor interaction(s) triggering specific signal transduction pathways. Examples of research areas of interest are described below. 1. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ALCOHOL INTAKE The association between stress and the onset of alcohol consumption is a well- recognized phenomenon, from which the term, "tension-reduction hypothesis of alcohol use" originated. Stress or single doses of alcohol stimulate the HPA axis, eliciting the release of corticotropin releasing factor (CRF) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and glucocorticoids from the adrenals. Paradoxically, chronic alcohol intake depresses all peptides associated with the HPA axis, including reduced cerebrospinal fluid levels of CRF, blunted ACTH responses to either naloxone or CRF, and decreased responsiveness of the adrenals to CRF or ACTH. The anatomical site(s) on which alcohol alters CRF levels remains to be determined, and may be strain- and/or species-specific. For instance, alcohol-preferring (P) rats have significantly lower CRF levels in the hypothalamus, amygdala and prefrontal cortex than non-preferring (NP) rats. Also, high alcohol intake in Wistar rats correlates with elevated hypothalamic CRF levels and depressed pituitary and pons CRF levels. Animal studies suggest a relationship between ACTH levels and alcohol consumption, with gender being a contributing factor (see review by Maickel and Sprague, 1995). Rats repeatedly injected with ACTH (but not stressed) exhibited comparable increases in alcohol consumption to post-stressed rats. Female Sprague-Dawley rats possess higher basal ACTH plasma levels and lower post-stress ACTH levels than males from this strain, and these values are predictive of relative alcohol intake patterns. In humans, plasma ACTH levels in non-alcoholic sons from alcoholic and non- alcoholic families differ. Family history positive (FHP) sons exhibit lower basal plasma ACTH levels and lower ACTH peak responses to CRF than their family history negative (FHN) counterparts. However, following dual administration of alcohol and CRF, peak ACTH levels in FHN subjects are reduced substantially but remain unchanged in FHP subjects. These findings are consistent with the general reduction in other responses to alcohol. More research is needed about the role of CRF and ACTH in regulating alcohol intake. Because of varied responses to alcohol by males and females, studies of gender differences are especially encouraged. In addition to the general areas of investigation described above, research is encouraged (but not limited) to: o Characterize the mechanisms by which alcohol interferes with CRF release. o Determine whether a reduced HPA response to alcohol in FHP sons could be a marker of susceptibility to alcoholism. 2. THE OPIOID SYSTEM AND ALCOHOL INTAKE Naltrexone, a non-selective opioid antagonist, is an FDA approved drug for treating alcoholism. However, the mechanisms by which it works are not clearly understood. Studies in animals and humans suggest that endogenous opioids may regulate alcohol consumption. Naltrexone and naloxone suppress alcohol consumption and attenuate intoxication observed in animals and humans (see review by Froehlich, 1993). Moreover, additional animal studies demonstrate that antagonists selective for mu or delta opioid receptors are likewise effective in reducing alcohol consumption. Finally, opioid receptors may regulate dopamine release in mesolimbic pathways and alcohol-seeking behavior. Both alcohol and opioids release dopamine from the nucleus accumbens through actions on opioid receptors. Naltrexone and its analogues antagonize alcohol-induced increases in dopamine release and reduce alcohol intake. Opioids may act as primers for further alcohol consumption. If ethanol exposure releases endogenous opioid peptides, a subject may be primed to continue drinking. When naltrexone is administered, this priming effect is inhibited. Thus, little incentive exists to consume more ethanol. Indeed, recent clinical studies support the rodent studies. Both alcoholics and nonalcoholics given naltrexone report being less high when they consume ethanol. These data suggest that abstinent alcoholics have fewer relapses because they are not obtaining the positive reinforcement they expect by ingesting ethanol. This effect can persist during the first six months after therapy is discontinued. Acute alcohol consumption increases endorphin and enkephalin gene expression, enhancing opioid release from brain and pituitary sites in rodents and humans. Despite contrary evidence that chronic alcohol consumption decreases opioid gene expression in regions of the rat brain and depresses beta-endorphin release in the brains of alcoholics, chronic alcohol intake nonetheless elevates opioid levels. The explanation for this sustained opioid elevation is a compensatory reduction in opioid enzymatic degradation. Thus, although acute and chronic alcohol exposures activate the endogenous opioid system by different means, they both reinforce sustained alcohol consumption. Congenital anomalies of the opioid system may predispose some individuals to over-consume alcohol. After human subjects ingest alcohol, their opioid systems become more responsive. However, after chronic ingestion of alcohol, their opioid systems become less responsive. Defective opioid systems have also been described in alcohol-naive ethanol-preferring inbred rodent lines and in children of alcoholics before they initiate alcohol-drinking behavior. At the molecular level, differences in opioid peptide content, opioid receptor density and opioid secretion were detected when alcohol-preferring mice were compared with alcohol-avoiding mice. Further research is needed to gain a better understanding of the role of opioid peptides in alcohol consumption. Studies are encouraged to include both genders. In addition to the general areas of investigation described above, research is encouraged (but not limited) to: o The mechanism(s) by which current opioid antagonists reduce relapses in alcoholics. o Development and testing of selective opioid receptor antagonists for their effects on alcohol consumption. 3. THE RENIN-ANGIOTENSIN SYSTEM AND ALCOHOL INTAKE Alcohol increases plasma osmolality without perturbing cellular osmotic homeostasis by rapid equilibration across cell membranes. Thus, single doses of alcohol induce diuresis and increased plasma volume. As a consequence, plasma angiotensin II (AII) levels rise. Chronic intake of alcohol produces a comparable effect. Plasma AII levels are significantly elevated in male rats fed alcohol for 50 days and significantly rise in actively drinking alcoholic men a few hours after taking a drink. Peripheral administration of AII significantly depresses alcohol intake in animals despite their excessive consumption of water. In addition, the co- administration of Losartan (an AII receptor antagonist) partially restores alcohol intake, but has no effect on water intake in animals. Interestingly, ethanol intoxication in the mouse (demonstrated by impaired aerial righting reflex) was substantially reversed by pre-treatment with Losartan and was completely abolished by a combination of Losartan and PD123319 (AT1 and AT2 receptor antagonists, respectively). An understanding of the mechanism by which these AII receptor antagonists abate the behavioral symptomatology of intoxication would be expected to stimulate development of novel therapeutic modalities. Various chemical manipulations known to elevate plasma levels of renin, a precursor of angiotensin II (e.g., isoproterenol, fluoxetine, prostaglandin E2, histamine, and inhibitors of angiotensin converting enzyme) likewise suppress ethanol intake in animals. NP rats have higher endogenous plasma renin levels than P rats, and Rapp rats homozygous for a mutant renin gene drink more alcohol than heterozygotes. Rats with experimentally induced renal hypertension develop high plasma renin levels and subsequently drink significantly less alcohol than sham controls. Based upon these data, an inverse relationship exists between plasma AII levels/renin activity and alcohol consumption (see review by Grupp, 1993). Further research is needed to gain a better understanding of the role of the RAS in alcohol consumption. Studies are encouraged to include both genders. In addition to the general areas of investigation described above, research is encouraged (but not limited) to: o Understanding the relationship between angiotensin II receptors and alcohol consumption/intoxification by evaluating levels in selective AII receptor (AT1 vs AT2) knock-out and over-expressing transgenic mice and in animals overexpressing AII. o Clarifying the relationship between angiotensin II and alcohol consumption (particularly inconsistencies between icv and peripheral administration), inducible transgenic mice overexpressing AII may be one means to accomplish this initiative. 4. FOOD INTAKE & ENERGY HOMEOSTASIS: LEPTIN, NPY, AND ALCOHOL INTAKE Alcohol and food intake are both appetitive and consummatory behaviors. Thus, there may be common mechanisms underlying uncontrolled eating and excessive alcohol intake. In recent years studies of body weight and energy balance in animals and humans have identified new peptides and hormones that regulate food intake. Some of these peptides, including leptin and neuropeptide Y (NPY), have been shown to modify alcohol consumption. For example, exogenous administration of leptin, a peptide which decreases food intake, reduces voluntary alcohol intake in male C57BL mice by half. Although NPY is an extremely potent orixigenic peptide (exogenous administration producing morbid obesity), C57BL NPY knock-out mice drink substantially more alcohol, and FVB transgenic mice overexpressing NPY (by 5-fold) drink significantly less alcohol than their matched controls. The NPY story is made even more interesting since both the knock-out and transgenic mice described above ate normal amounts of food and maintained normal body weights, and by the confirmatory report that P rats have significantly lower levels of NPY in the brain than NP rats. Leptin interacts with the arcuate nucleus of the hypothalamus. Leptin up- regulates proopiomelanocortin (POMC) via alpha-melanocyte stimulating hormone (alpha-MSH) and its MC-4 receptor, and down regulates both agouti-related proteins (AGRP) and NPY. Alpha-MSH down-regulates melanin concentrating hormone (MCH) in the lateral hypothalamus and diminishes MCH"s impact on various prefrontal cortical sites. The down-regulation of NPY by leptin occurs in the paraventricular nucleus, modulating CRF and thyrotropin releasing hormone (TRH), and impacting upon various sympathetic and parasympathetic regulatory pathways (see review by Friedman, 1998). Other peptides have been examined for their effects upon alcohol intake. The administration of three peptides (cholecystokinin, bombesin and the tachykinins) depressed alcohol intake, whereas three others (vasoactive intestinal peptide, galanin, and beta-endorphin) increased alcohol intake. Three were ineffective, including neurotensin, somatostatin, and enterostatin. Further research is needed to gain a better understanding of the role of food intake/energy expenditure peptides in alcohol consumption. Studies are encouraged to include both genders. In addition to the general areas of investigation described above, research is encouraged (but not limited) to: o Determining whether alcohol consumption is regulated by other proteins and hormones such as AGRP, MCH, alpha-MSH, cocaine- and amphetamine-regulated transcript (CART) peptide, and the orexins. o Studying alcohol consumption with various rodent models of obesity [e.g., models of leptin deficiency such as the obese (ob) mouse, or the diabetic (db) mouse, which is deficient in the leptin receptor], or available double knock- out mice (i.e., leptin and NPY). o Investigating the apparent discordance between the pharmacologic and genetic findings involving NPY as they relate to alcohol consumption, food intake, and weight regulation. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994, (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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 these policies. LETTER OF INTENT For the first receipt date of December 22, 1999, only, prospective applicants are asked to submit, by November 24, 1999, 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 PA in response to which the application may be submitted. A letter of intent is not requested for applications submitted for subsequent receipt dates. 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 NIAAA staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Peptide PA Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4375 FAX: (301) 443-6077 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. 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, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, Email: grantsinfo@nih.gov. The PA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Page limits and limits on size of type are strictly enforced. Non-conforming applications will be returned without being reviewed. 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, reviewer"s and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year for R01s, $100,000 per year for R21s, and $50,000 per year for R03s. (Applications for R01s that request more than $250,000 for direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments and Total Costs) [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm . - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, and - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this PA and will be returned without further review. The title and number of the program announcement must be typed in Section 2 on the face page of the application. For the first receipt date only, 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, for the first receipt date only, two additional copies of the application must also be sent to: Peptide PA Office of Scientific Affairs 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) Applications for the first receipt date must be received by December 22, 1999. Standard application receipt dates will be used thereafter. All five copies of an application for a standard receipt date must be sent to the Center for Scientific Review as described in the PHS-398 application instructions. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by the NIAAA. Incomplete applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit by an appropriate peer review group in accordance with the review criteria stated below. As part of the initial merit review, a process will 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 a 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. Significance: Does the study address the goals of the PA? If the aims of the study are achieved, how will scientific knowledge be advanced? Will the study advance the concepts or methods that drive this field? 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 designs? Feasibility: Can the design be implemented (including recruitment of subjects, cooperation of relevant organizations, and/or collection of necessary data)? Innovation: Does the project employ novel concepts, approaches, theories, or methods? Investigator: Are the principal investigator and key research personnel appropriately trained and well-suited to carry out this work? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Does the proposed research take advantage of the unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Budget: Is the requested budget and estimation of time to completion of the study appropriate for the proposed research? In addition, plans for the recruitment and retention of subjects will be evaluated as well as the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications recommended for approval by the National Advisory Council on Alcohol Abuse and Alcoholism will be considered for funding on the basis of the overall scientific and technical merit of the proposal as determined by peer review, NIAAA programmatic needs and balance, and the availability of funds. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jules R. Selden, V.M.D., Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 Telephone: (301) 443-2678 FAX: (301) 594-0673 Email: jselden@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Linda Hilley Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 FAX: (301) 443-3891 Email: lhilley@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 the authorization of the Public Health Service Act, Sections 301 and 464H, and administered under the NIH policies and Federal Regulations at Title 42 CFR Part 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. REFERENCES Friedman JM: Leptin, leptin receptors, and the control of body weight. Nut Revs 56:S38-S46, 1998. Froehlich JC: Interactions between alcohol and the endogenous opioid system. (S. Zakhari, ed.). In, Alcohol and the Endocrine System, NIAAA Research Monograph No. 23, pages 21-35, 1993. Grupp LA: The renin-angiotensin system as a regulator of alcohol consumption: a review and some new insights. (S. Zakhari, ed.). In, Alcohol and the Endocrine System, NIAAA Research Monograph No. 23, pages 37-65, 1993. Maickel RP, Sprague JE: Role of ACTH fragments in alcohol consumption. (WA Hunt and’s Zakhari, eds.). In, Stress, Gender, and Alcohol-Seeking Behavior, NIAAA Research Monograph No. 29, pages 167-180, 1995.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.