MECHANISMS OF ALCOHOL-INDUCED HEPATIC FIBROSIS Release Date: June 14, 1999 PA NUMBER: PA-99-110 National Institute on Alcohol Abuse and Alcoholism THIS 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 Division of Basic Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites grant applications that focus on the developmental mechanisms of hepatic fibrosis that occur in alcohol-induced liver disease. Cirrhosis is the eleventh leading cause of death in the United States. It is estimated that approximately 50 percent of all deaths due to cirrhosis involve alcohol abuse and alcoholism. Alcoholic liver disease encompasses a spectrum of liver pathology that progresses from steatohepatitis to cirrhosis and hepatocellular carcinoma. Cirrhosis is the end stage liver disease developing from long term hepatic fibrogenesis. Hepatic fibrogenesis is a process where excessive deposition of extracellular matrix components, especially collagen, occurs due to an imbalance between the amount of matrix macromolecules produced versus degraded in the liver. Considerable evidence implicates hepatic stellate cells (HSC) as the primary source of excessive extracellular matrix in liver fibrosis. A major feature of fibrosis is the activation of HSC, consisting of an early initiation phase followed by a perpetuation phase. Upon activation, HSC undergo transformation and mediate microenvironmental changes in the liver that include the loss of vitamin A, acquisition of contractility, perisinusoidal matrix degradation, cellular migration and proliferation and increased matrix production and accumulation. Understanding the developmental, molecular, biochemical and microenvironmental changes that occur in the hepatic macromolecular extracellular matrix and cellular constituents of the liver resulting in the pathological sequelae of hepatic fibrosis are fundamental to design strategies for the prevention and treatment of the disease. 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 national activity for setting priority areas. This PA, Mechanisms of Alcohol-Induced Hepatic Fibrosis, is related to the priority areas of alcohol-associated medical disorders. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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. Foreign institutions are not eligible to apply for Small Grant (R03) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research project grant (R01) and the NIAAA Small Grant (R03) Program mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 application submitted in response to this PA may not exceed 5 years. The NIAAA Small Grants (R03) are for no longer than 2 years and no more than $50,000 direct costs per year. The NIAAA Small Grant (R03) Program has specific application formats and review criteria. Applicants are strongly encouraged to consult with program staff listed under INQUIRIES to obtain the program announcement for the NIAAA Small Grant Program (PAR-99-098). The applicant may also obtain the program announcement on the NIAAA home page at 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 Grant applications can be found at http://www.nih.gov/grants/funding/modular/modular.htm RESEARCH OBJECTIVES BACKGROUND: Areas of Interest The major objective of this Program Announcement is to solicit both basic and pre-clinical research applications that address the developmental progression of alcoholic liver disease from steatohepatitis to cirrhosis and hepatocellular carcinoma with a specific emphasis on stellate cells and their activation. Basic studies that develop new animal models of liver disease relevant to disease progression or utilize current animal models to elucidate cellular, molecular or microenvironmental changes related to disease progression in alcoholic liver disease are encouraged. Pre-clinical studies that provide novel insights or propose new hypotheses related to human alcoholic liver disease are sought. Examples of focused areas of research include, but are not limited to the following: Vitamin A: Vitamin A (retinol) and its metabolite retinoic acid play an important role in the regulation of cell proliferation and cell differentiation. The activation of HSC is associated with the loss of cellular content of vitamin A. On the other hand, treatment with retinoids suppress HSC proliferation, decrease gene expression of collagen as well as TGF-beta and thereby attenuate liver fibrosis. These findings suggest an inhibitory effect of vitamin A on HSC activation and associated liver fibrosis. However, the underlying molecular and biochemical mechanisms of this effect of vitamin A are not clear. In the bile duct ligation model of hepatic fibrosis, increased mRNA levels of procollagen alpha-1(I) and TGF-beta were associated with diminished retinoic acid signaling in HSC as shown by decreased mRNA levels of retinoic acid receptor-beta, retinoid X receptor, and cellular retinol binding protein. Whether diminished retinoic acid signaling is causally related to increased collagen production needs investigation. Also, whether a similar mechanism exists in alcohol-induced hepatic fibrosis model remains to be determined. A central question in this line of research is: Can vitamin A prevent or down-regulate HSC activation and by what mechanism(s)? Acetaldehyde: Acetaldehyde, an immediate metabolite of ethanol, has been implicated in the development of hepatic fibrosis by increased collagen production. Acetaldehyde is primarily produced in hepatocytes and can diffuse out to interstitial space and affect HSC. Indeed it has been shown to increase collagen production by cultured rat HSC in vitro by increasing the transcription of alpha-1(I) collagen gene. At the same time, acetaldehyde decreased the synthesis of matrix metalloproteinases-1, an enzyme known to degrade type I collagen, thus promoting the accumulation of collagen in the liver. Acetaldehyde also increases the expression of other extracellular matrix components, including type III collagen and fibronectin. Acetaldehyde increased cell membrane-associated PKC activity of HSC, whereas PKC inhibitors blocked acetaldehyde-mediated alpha-1(I) collagen gene up regulation, suggesting a role of this kinase in transducing the intracellular signal. However, subsequent steps involved in the signal transduction pathways are not clear. Furthermore, the molecular mechanisms whereby acetaldehyde up-regulates the transcription of genes for collagen and other matrix proteins are not well understood. Salient questions that can be addressed are: Does acetaldehyde initiate or perpetuate HSC activation? What are the biological mechanisms that mediate acetaldehyde regulation of extracellular matrix deposition? Do exogenous factors or genetic expression predispose HSC to activation by acetaldehyde? Lipid Peroxidation: Chronic alcohol ingestion is associated with oxidative stress as reflected by increased hepatic levels of lipid peroxidation products such as malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). MDA and 4-HNE have been implicated in hepatic fibrogenesis in the intragastric ethanol infusion model of liver fibrosis and in the bile duct ligation model of liver fibrosis. Furthermore, lipid peroxidation products have been shown to induce gene expression of procollagen alpha-1(I) and increase collagen production by several folds in cultured HSC. However, other investigators have found a minimal and only transient effect of lipid peroxidation products. Studies are required to clarify whether lipid peroxidation products can activate quiescent HSC to produce increased collagen and identify the molecular and signal transduction pathways involved. Iron: Iron is known to play a key role in the development of hepatic fibrosis probably via oxidant stress and lipid peroxidation. Iron has been shown to exacerbate the effects of alcohol on liver disease. In intragastric infusion model of alcoholic liver disease (ALD), supplementation of carbonyl iron (0.25 percent) advanced perivenular fibrosis to bridging fibrosis and cirrhosis. This potentiating effect was associated with increased lipid peroxidation which may be an initial step by which excess iron induces fibrosis. The dietary iron supplementation was also associated with increased NF-kB activation, up regulation of NF-kB responsive proinflammatory genes such as TNF, and MIP-1, and mononuclear inflammation which has been implicated in initiating fibrogenesis. In this model of ALD, even without iron supplement, hepatic macrophages showed increases in iron content, NF-kB activation, and TNF and MIP-1 mRNA expression. All of these effects were abrogated by ex vivo treatment of the cells with an iron chelator, deferiprone, suggesting the role of iron in NF-kB activation and associated inflammatory cascade. Thus, iron may activate HSC via NF-kB activation and inflammation. Investigations are sought to determine iron absorption and transport in individuals with ALD. Studies are required to determine the mechanism(s) by which chronic ethanol intake sequesters iron in the macrophages. Can iron chelator therapy attenuate alcohol-induced liver fibrosis? Cytokines: Alcohol ingestion is known to stimulate production of a myriad of cytokines from hepatic cells, which have been implicated in the different stages of ALD through activation of HSC. Cytokines implicated in the loss of vitamin A by HSC are TNF and PDGF; matrix degradation can be mediated by TNF and IL-1; cellular migration may be mediated by PDGF; cell proliferation cytokine are PDGF, TGF-alpha, IL-1, and TNF; matrix accumulation cytokines are TGF-beta, IL-6, and TNF. Studies are needed to understand the molecular mechanisms by which these cytokines stimulate the different stages of fibrogenesis. Do these cytokines act independently or interact with each other before eliciting their effect on HSC? Are these cytokines released in latent forms that require activation before affecting HSC? TGF-beta is a major cytokine implicated in liver fibrogenesis by increasing matrix production. TGF-beta can indirectly enhance HSC proliferation by increasing the expression of PDGF. In addition, TGF-beta can enhance autocrine production in HSC. Thus, once TGF-beta is secreted, it can perpetuate both HSC proliferation and increased matrix production. It is not clear what mechanism(s) induces TGF- beta production by alcohol ingestion. One possibility is through increased lipid peroxidation and NF-kB activation. Leukocytes: Alcohol-induced hepatic fibrosis is generally preceded by inflammation that is associated with parenchymal infiltration of leukocytes (neutrophils and lymphocytes), which may activate HSC in a paracrine manner. Studies are needed to understand the role of leukocytes on HSC activation and subsequent accumulation of extracellular matrix. Increased release of reactive oxygen species and associated lipid peroxidation appears to be a primary mechanism by which neutrophils can stimulate increased collagen production by HSC. Neutrophils can also release proteases, which can digest laminin, an extracellular matrix protein, which helps maintain HSC in a quiescent state. Whether these cells can release cytokines in appreciable amounts capable of HSC activation remains to be investigated. It is also unclear whether these cells act upon HSC directly as well as through hepatocytes. The role of lymphocytes in HSC activation is variable depending upon the type of cytokine secreting-helper T cells. While TH2 cytokine secreting cells may promote fibrogenesis via the secretion of TGF-beta and IL-4, TH1 secreting cells may inhibit fibrogenesis through the secretion of gamma interferon. Studies are required to determine whether gene activation of cytokines and matrix molecules (e.g., chemokines, adhesion molecules) mediate cellular infiltration and thereby modulate fibrogenesis. Intracellular Signaling Pathways: Increasing evidence suggests that mediators activating HSC such as cytokines, acetaldehyde, and lipid peroxidation products utilize or initiate intracellular signaling pathways. The following signaling pathways have been identified in activated HSC: mitogen-activated protein (MAP) kinase, protein kinase C (PKC), phosphotidylinositol (PI) 3- kinase, and focal adhesion kinase (FAK). The MAP kinase family has two important members: the extracellular signal-regulated kinase (ERK) and c-jun terminal kinase (JNK). PI-3kinase and ERK are involved in PDGF-mediated HSC proliferation. Activities of ERK and JNK are increased by fibronectin and TNF during HSC activation. Activation of these cell signaling pathways and their resultant modification of cellular function in ALD could be the basis for therapeutic interventions. For example, treatment of rat HSC with a selective PKC inhibitor significantly suppressed alpha smooth muscle actin expression and cell proliferation. Could such an inhibitor be utilized in ALD? Transcription Factors: Several transcription factors are involved in the gene expression of matrix molecules produced by activated HSC during hepatic fibrogenesis. The factors implicated in the transcription of collagen genes are Sp1, Sp3, Zf9, NF-I, USF1, USF2, and NF-kB. Some of these factors such as Sp1, Sp3, and NF-kB are also involved in gene expression of biglycans, which are proteoglycan extracellular matrix proteins. Transcription factors implicated in HSC proliferation are AP-1 and c-myb. Studies are required to understand the molecular mechanisms and environment of gene expression as related to fibrogenesis and ALD. Identification and characterization of gene regulatory pathways involved in the initiation of HSC activation and extracellular matrix deposition could have application to novel therapeutic approaches such as gene therapy. Matrix Metalloproteinases (MMPs) and their Tissue Inhibitors (TIMPs): Excess collagen deposition in the liver results from an imbalance between the amount of collagen produced and the amount degraded by MMPs, a family of proteolytic enzymes with diverse specificity for different extracellular matrix components. Limited information is known regarding gene regulation and expression of the MMPs. HSC are known to express MMPs that degrade type I and IV collagens. In individuals with ALD, liver collagenase activity was shown to be increased at early stages of the disease, but was decreased or absent in advanced cirrhosis. This may, in part, be responsible for the initial perisinusoidal matrix degradation that is followed by excess collagen accumulation in hepatic fibrosis. Studies are required to understand the physiology of MMP induction and pathology induced by aberrant production. Investigation of the mechanism(s) that control the genetic expression of these enzymes and their enzymatic activity are needed. This includes a study of increased levels of TIMPs that can result in excess accumulation of extracellular matrix proteins by inhibiting the activities of MMPs. In fact, increased expression of mRNA for TIMP-1 and TIMP-2 and increased synthesis of associated proteins have been shown in cultured activated HSC. Similar results have been shown in animal models of liver fibrosis and in human liver disease. TIMP-1 levels are also increased in ALD where the cellular source is activated HSC. Furthermore, in ALD patients, the levels of TIMP-1 correlate with the severity of the disease. Studies are needed on expression of various TIMPs in ALD in its various clinical forms and stages. Also the mechanisms by which alcohol increases TIMP-1 expression need to be elucidated. This could be a direct effect of alcohol or mediated through acetaldehyde, alcohol-induced oxidant stress, or cytokine activation. Therapeutic Interventions: Basic and pre-clinical research applications are encouraged to develop therapeutic interventions for the treatment and prevention of alcohol-induced liver disease. A particular focus is on the inhibition of progression of liver fibrosis to cirrhosis and associated hepatocellular carcinoma. In this regard, some progress has been made by administering polyunsaturated lecithin and its active components. For example, in baboons, administration of polyenylphosphatidylcholine (PPC) prevented alcohol-induced septal fibrosis and cirrhosis which was associated with decreased number of activated HSC. This effect of PPC was mediated through decreased oxidant stress and increased collagen breakdown via increased collagenase activity. The uses of antioxidants such as vitamin A, vitamin E and S-adenyl methionine (SAM), a precursor of glutathione, have yielded mixed results. Further studies are needed to investigate candidate molecules related to oxidant stress and fibrosis and their administration or delivery system (e.g., liposomes, viral vector) as well as targeted cell type(s). Additionally, anticytokine agents such as TGF-beta and PDGF antibodies, soluble receptors, and antisense oligonucleotides need to be experimentally investigated in animal models of alcoholic liver disease to produce new paradigms for therapy. 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, Vol. 23, No. 11, March 18, 1994, available on the web at the following URL address: https://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://www.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. APPLICATION PROCEDURES Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding their proposed project. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted on the standard receipt dates indicated in the application kit. Application kits 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) 710-0267, Email: grantsinfo@nih.gov. Applications are also available on the World Wide Web at: http://www.nih.gov/grants/forms.htm. 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 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 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 - Use a Modular Grant Budget Narrative page. (See http://www.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. 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. 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. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. 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://www.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. - 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. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. 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. 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 program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the staff that the Institute 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 who agreed to accept assignment of the application. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board, when applicable. 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. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priorities. 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: Vishnudutt Purohit, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2689 FAX: (301) 594-0673 Email: vpurohit@willco.niaaa.nih.gov Leslie Isaki, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 594-6228 FAX: (301) 594-0673 Email: lisaki@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, Suite 504, 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 authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241, 285, and 290) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 or Part 92, as appropriate. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). The PHS strongly encourages all grant and contract 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, and 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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