S-ADENOSYL-L-METHIONINE (SAME) AND LIVER DISEASE RELEASE DATE: January 30, 2002 RFA: RFA-AA-02-011 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) The Office of Dietary Supplements (ODS) (http://www.nih.gov/icd/od) The National Center for Complementary and Alternative Medicine (NCCAM) (http://www.nccam.nih.gov) LETTER OF INTENT RECEIPT DATE: April 15, 2002 APPLICATION RECEIPT DATE: May 15, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Where to send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE The purpose of this RFA is to invite applications for grants proposing innovative basic and preclinical research to understand how SAMe may be effective in the treatment of liver disease caused by alcohol and other factors such as hepatitis C virus (HCV). Liver disease progresses from steatohepatitis to fibrosis, and cirrhosis, which is a major cause of illness and death in the USA. Oxidant stress plays a key role in pathogenesis of liver disease. SAMe, a dietary supplement, is a methyl donor for biochemical methylation reactions and a precursor of glutathione, the main hepatocellular antioxidant. SAMe has been shown to attenuate liver injury caused by alcohol and other hepatotoxins in animal models, and these changes were associated with restoration of depleted hepatic glutathione levels. Understanding the mechanisms by which SAMe attenuates liver injury caused by alcohol and/or HCV, or other hepatotoxins may provide useful information for full-scale human clinical trials. RESEARCH OBJECTIVES Liver disease characterized by fatty liver, hepatitis, fibrosis, and cirrhosis is a major cause of illness and death worldwide. It is the fourth leading cause of death among adult men of 24-65 years residing in urban areas of the USA. Women are more susceptible to alcohol induced liver damage than men and develop alcoholic liver disease at a more rapid rate having imbibed less alcohol. Approximately 50% of all deaths due to liver cirrhosis involve alcohol abuse and alcoholism. Alcoholic liver disease is exacerbated by HCV infection, which is a worldwide health problem, affecting approximately 170 million persons. Those who abuse alcohol are more easily infected with HCV and are more likely to experience persistent, long-term infection. Excessive alcohol consumption increases viral burden and interferes with antiviral therapy. Their liver disease is more likely to progress to cirrhosis and hepatocellular carcinoma. Currently HCV is treated with interferon plus ribavirin, a combination, which has multiple drawbacks that limit its usefulness. Current therapies are effective in clearing the HCV virus in only 30-40% of the cases. Recent research indicates that oxidant stress is in part responsible for the liver damage seen in HCV infection. SAMe may be a useful adjunct in the treatment of HCV. Various factors have been implicated in the initiation of liver injury, such as endotoxin, tumor necrosis factor-alpha (TNF-alpha), and free radicals. Free radicals can activate nuclear transcription factor-kB (NF-kB), which increases the transcription of TNF-alpha, a proinflammatory cytokine that can initiate hepatitis. Several sources of free radicals, including NADPH oxidase, xanthine oxidase, CYP2E1, and lipooxygenase, have been identified in Kupffer cells of the liver. Using animal models and cultured liver cells, researchers have established a firm link between generation of free radicals and development of alcohol-induced liver injury. Thus, complementary and alternative approaches that diminish oxidant injury may have merit in terms of protecting the liver from free radical induced damage. Researchers have investigated the roles of dietary supplements, having antioxidant properties, in the treatment of liver disease caused by different agents including alcohol. Antioxidants that are being studied include N- acetylcycteine, vitamin E, polyenylphosphatidylcholine, and silymarin. The potential usefulness of the SAMe in liver disease is based on the following information. 1) SAMe is a precursor of glutathione, which is an endogenous antioxidant. 2) Chronic ethanol intake depletes hepatic SAMe levels that are associated with impaired metabolism of methionine, a precursor of SAMe. 3) SAMe has been shown to attenuate hepatotoxicity caused by TNF-alpha, which is known to trigger alcoholic hepatitis. 4) In animal models, SAMe administration restored mitochondrial glutathione depletion and attenuated liver injury caused by alcohol and other hepatotoxins. Possible topics responsive to this RFA include, but are not limited to: o Investigation of the mechanisms by which hepatotoxic agents, including alcohol, impair methionine (SAMe precursor) metabolism and its impact on hepatic SAMe and glutathione levels? o Identification of the role of folate deficiency in methionine metabolism, and ultimately SAMe and glutathione levels. o Investigation of the mechanisms by which hepatototxins deplete hepatic mitochondrial glutathione levels and impair mitochndrial functions, and the role of SAMe in restoring these defects. O Determination of whether providing supplemental SAMe affects circulating and cellular levels of glutathione. Study the pharmacokinetics of SAMe in animal models. o Investigation of the mechanisms by which impaired SAMe synthesis predisposes to liver injury. Is it due to hypomethylation and/or oxidant stress caused by depressed glutathione levels, or by other mechanisms? o Determination of whether SAMe levels influence the activation of NF-kB and/or gene expression of TNF-alpha and other inflammatory cytokines. o Elucidation of the stages of liver disease that are more responsive to SAMe treatment o Exploration of whether SAMe affects immune functions, and whether this immune modulation by SAMe has a salutary effect on liver function. o Investigation of the potential of SAMe for use as adjunctive therapy for hepatitis C and whether this approach would make the present therapy more effective and better tolerated. o Investigation of whether SAMe diminishes virally-induced liver damage and modifies the progression of HCV-related liver disease. MECHANISMS OF SUPPORT This RFA will use NIH research project grant (R01), exploratory/developmental grant (R21), and small grant (R03) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 28, 2002. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. FUNDS AVAILABLE The participating ICs intend to commit approximately $1.5 million in FY 2002 to fund 6 to 10 new and/or competitive continuation grants in response to this RFA. Applicants for R01s may request a project period of up to 5 years and a budget for direct costs of up to $250,000 per year. 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. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the ICs 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: O Direct your questions about scientific/research issues related to alcohol abuse and alcoholism to: Vishnudutt Purohit, Ph.D. Program Director 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) Telephone: (301) 443-2689 FAX: (301) 594-0673 Email: vpurohit@willco.niaaa.nih.gov O Direct your questions about scientific/research issues related to complementary and alternative medicine to: Marguerite Evans Program Officer National Center for Complementary and Alternative Medicine 6707 Democracy Blvd. Democracy 2, Suite 401 Bethesda, MD 20892-5475 Telephone: 301-402-5860 FAX: 301-480-3621 Email: me16o@nih.gov or evansm@mail.nih.gov O Direct your questions about scientific/research issues related to dietary supplements to: Rebecca B. Costello, Ph.D. Office of Dietary Supplements Office of Disease Prevention, Office of the Director Building 31, 1B29 Bethesda, MD 20892 Phone: 301-435-2920 Fax: 301-480-1845 Email: CostellB@od.nih.gov O Direct your questions about financial or grants management matters to: Judy Fox Simons Acting Chief, 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 LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 by the date listed at the beginning of this document. The letter of intent should be sent to: Extramural Project Review Branch ATTN: AA-02-011 Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 (for express mail, use Rockville, MD 20852) SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: 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. SENDING AN APPLICATION TO THE NIH: 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 and five copies of any appendix material must be sent to: Extramural Project Review Branch ATTN: AA-02-011 Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 (for express mail, use Rockville, MD 20852) APPLICATION PROCESSING: 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the appropriate IC. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NIAAA or NCCAM National Advisory Council. 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well-suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 15, 2002 Application Receipt Date: May 15, 2002 Peer Review Date: July - August, 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 28, 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. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. 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. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA 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. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.273, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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. The Office of Dietary Supplements (ODS) was mandated by Congress in 1994 and established within the Office of the Director, National Institutes of Health (NIH). The Dietary Supplement Health and Education Act (DSHEA) [Public Law 103-417, Section 3.a] amended the Federal Food, Drug, and Cosmetic Act "to establish standards with respect to dietary supplements." This law authorized the establishment of the ODS.

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