ALCOHOLIC HEPATITIS: CELLULAR AND MOLECULAR MECHANISMS RELEASE DATE: March 14, 2002 PA NUMBER: PA-02-078 EXPIRATION DATE: March 15, 2005, unless reissued. National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) seek grant applications to study the underlying cellular, biochemical, and molecular mechanisms by which chronic ethanol ingestion leads to the initiation and development of alcoholic hepatitis. Left untreated, this condition could further progress to hepatic cirrhosis, which is a major cause of death in this country. Chronic hepatitis C infection (1.8% of the US population) along with the alarming increases in overweight and obesity across all ages, racial and ethnic groups, and both genders (61% adults and 13% children) are significant causes of liver morbidity. The institutes are also interested in research that elucidates interactions between alcohol and either HCV infection, obesity, or nutritional deficiencies which can potentiate the severity, and accelerate the course of alcoholic hepatitis. Understanding the mechanisms may help to design strategies for the effective prevention and treatment of the disease. RESEARCH OBJECTIVES Alcoholic liver disease (ALD) is a major cause of illness and death in the USA. It is the fourth leading cause of death among adult men of 24- 65 years residing in urban areas. 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. This disease is characterized by fatty liver, hepatitis, fibrosis, and cirrhosis. Cirrhosis is the eleventh leading cause of death in this country. Approximately 50% of all deaths due to liver cirrhosis involve alcohol abuse and alcoholism. Up to 35 percent of heavy drinkers develop alcoholic hepatitis, though the condition is often unrecognized and poorly diagnosed. The clinical features of alcoholic hepatitis may include abdominal pain, fever, jaundice, and liver failure. The disease can progress to cirrhosis and even hepatocellular carcinoma. Histopathologically, it is characterized by liver cell death and infiltration of leukocytes into the hepatic parenchyma. Although many treatments are being used for the amelioration of alcoholic hepatitis, none of them are effective. To develop an effective treatment for this disease, it is important to understand the underlying mechanisms by which chronic alcohol ingestion triggers the development of the inflammatory disease process. Researchers have made significant progress in understanding the mechanisms of alcohol-induced early liver injury. Alcohol is thought to render the intestinal wall more permeable to endotoxin. This results in increased amount of bacterial endotoxin in hepatic portal system, which activates Kupffer cells of the liver via the CD14 surface receptor. This activation initiates a cascade of events leading to increased generation of free radicals, activation of nuclear transcription factor-kB (NF-kB), increased transcription of inflammatory cytokines and chemokines, increased expression of adhesion molecules, and increased infiltration of inflammatory cells into the liver. These changes are associated with the histopathological findings of fatty liver, patchy necrosis, and mild inflammation of the liver. Despite this progress in our understanding of ALD, the mechanisms by which chronic ethanol consumption results in alcoholic hepatitis in humans are not clear. This Program Announcement addresses the following issues: 1) role of Kupffer cells in triggering the process of inflammation; 2) types of leukocytes that are involved in the pathogenesis of alcoholic hepatitis; 3) the chemokines that are responsible for the attraction of leukocytes into the liver; 4) the adhesion molecules that promote the attachment of leukocytes to endothelial cells and hepatocytes; 5) the mechanisms of leukocyte transmigration into the hepatic parenchyma; 6) the mechanisms by which leukocytes initiate tissue injury (free radicals vs. proteases); 7)the mechanisms of interactive effects of alcohol, HCV, and HIV on the progression of hepatitis; 8)interaction between alcohol and overweight/obesity; 9) the role of nutrient deficiencies; and 10) potential targets of interventions for the disease. Appropriate topics for investigation under this PA would include, but are not limited to: o Investigation of the mechanisms by which Kupffer cell-generated inflammatory mediators injure endothelial cells and hepatocytes, and stimulate migration of leukocytes into hepatic parenchyma. o Elucidation of the mechanisms by which neutrophils, monocytes and lymphocytes are activated in hepatic sinusoids, attach to endothelial cells, and pass through the cell lining into the hepatic parenchyma. o Determination of the types and cellular sources of chemokines and adhesion molecules involved in attracting leukocytes and their attachments at different stages of inflammation. Can blocking the synthesis of chemokines and adhesion molecules arrest the inflammatory process? o Exploration of the mechanisms of peripheral blood mononuclear cell activation in response to chronic ethanol ingestion. o Determination of which cell type neutrophil, monocyte or lymphocyte initiates damage to hepatocytes. Do these cells interact in a coordinated fashion to damage hepatocytes? o Investigation of how neutrophils, monocytes and lymphocytes attach to hepatocytes and injure or kill these cells directly. o Determination of the subsets of neutrophils, monocytes and lymphocytes whose function may be compromised by ethanol, making the liver more susceptible to injury by alcohol. o Elucidation of the internal cellular mechanism(s)hepatocytes may use to cause self-injury. o Investigation of whether hepatocyte injury is mediated through increased ethanol metabolism-associated oxidant stress, cytokine- induced cell death, or chemokine-induced recruitment of inflammatory cells. o Determination of how alcohol intake increases the severity of HCV- induced liver injury. Investigation of alcohol's effect on promoting viral replication, or inhibiting viral clearance is encouraged. o Determination of the impact of HIV infection on the pathogenesis of alcoholic hepatitis. o Investigation of the role of nutrient deficiencies in the pathogenesis of alcoholic liver injury, and on the tissue injury repair process. o Study the interaction between alcohol and obesity on the progression from injury to repair in hepatocytes. o Characterization of biomarkers that can be used for early diagnosis of alcoholic hepatitis. o Identify and test potential targets of interventions for the disease, such as inhibition of alcohol-inducible enzymatic activity (i.e CYP2E1) involved in the generation of free radicals, as well as new anti- inflammatory and antiviral drugs. MECHANISM(S) OF SUPPORT This PA will use the NIH research project grant (R01) small grant (R03) and Exploratory/developmental grant (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period for a research project grant (R01) application submitted in response to this Program Announcement may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA-99-131, "NIAAA Exploratory/Developmental Grant Program," https://grants.nih.gov/grants/guide/pa-files/PA-99- 131.html, for a complete description of the R21 mechanism.) Under the NIAAA Small Grant mechanism (R03) applicants may request either $25,000 or $50,000 in direct costs per year for up to two years. These awards are not renewable; however, a no-cost extension of up to one year may be granted to the grantee institution prior to expiration of the project period. Before completion of the R03, investigators are encouraged to seek continuing support for research through a research project grant (R01). (See Program Announcement PA- 99-098, "NIAAA Small Grant Program," https://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, for a complete description of the R03 mechanism.) This PA uses just-in-time concepts. It also uses the modular budgeting format. (see https://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. 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 your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues 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 Jose Serrano M.D., Ph.D. Director Liver & Biliary and Pancreas Programs Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 657, MSC 5450 BETHESDA MD 20892-5450 (For Courier service use: 6707 Democracy Blvd, Room 657 BETHESDA MD 20817) Telephone: (301) 594-8871 FAX: (301) 480-8300 Email: SerranoJ@extra.niddk.nih.gov o Direct your questions about financial or grants management matters to: Judy Fox Simons 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) 443-4704 Email: jsimons@willco.niaaa.nih.gov Donita Marconi Grants Management Specialist National Institute of Diabetes, Digestive and Kidney Diseases Two Democracy Plaza, Room 710 Bethesda, MD 20892-5456 (for express mail, use Rockville, MD 20852) Telephone: (301) 594-8860 Email: Marconid@extra.niddk.nih.gov 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at https://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. 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 https://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 https://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate national advisory council or board 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: 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. 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) DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20 01.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 https://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 https://grants.nih.gov/grants/guide/notice- files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA 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 PA 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 https://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.
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