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MECHANISMS OF ALCOHOLIC PANCREATITIS RELEASE DATE: October 08, 2003 PA NUMBER: PA-04-005 EXPIRATION DATE: This Announcement expires on October 15, 2006 unless re-issued. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.273 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 THE PA The National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Institute on Drug Abuse (NIDA) are seeking research grant applications that will investigate the underlying molecular, biochemical, and cellular mechanisms by which long-term alcohol ingestion leads to the development of pancreatitis. Research is also encouraged to understand the role of various predisposing factors, including substance abuse, that make the pancreas susceptible to alcoholic injury. Understanding the mechanisms as well as the role of predisposing factors may help in developing strategies for the prevention or treatment of the disease. RESEARCH OBJECTIVES Background: Long-term heavy alcohol consumption is associated with both acute and chronic pancreatitis. Acute pancreatitis is characterized by pain, edema, hemorrhage, acinar cell vacuolation, necrosis and increased serum levels of amylase and lipase. Chronic pancreatitis is characterized by features of acute pancreatitis superimposed on a background of chronic changes that include fibrosis, inflammation, some level of calcification, and loss of exocrine tissue. Progression of pancreatitis may lead to multiple co-morbidities including maldigestion, diabetes, and pancreatic cancer. A recent advance in our understanding of pancreatitis is the development of animal models of alcoholic pancreatitis using co-factors such as cholecystokinin-8 (CCK- 8), unsaturated fat, and viral infection. However, further refinement is required in the development of animal models of pancreatitis that more closely mimic human conditions. Premature activation of zymogens (inactive digestive enzymes) within the pancreatic acinar cell results in the release of active enzymes within pancreatic tissue, leading to autodigestion that may initiate pancreatitis. Cerulin, an analogue of CCK has been shown to cause zymogen activation in a time- and dose-dependent manner in pancreatic acinar cells, an effect which is enhanced by alcohol. Moreover, ethanol increased rat pancreatic amylase secretion and plasma CCK levels, which were mediated through CCK-releasing factor. Further research is required to understand the interactive effect of alcohol and CCK on zymogen activation. The pancreas can metabolize ethanol via oxidative as well as non- oxidative pathways, generating acetaldehyde and fatty acid ethyl esters (FAEE), respectively. The major oxidative enzyme system employs alcohol dehydrogenase (ADH), and the non-oxidative pathway utilizes FAEE synthases. Acetaldehyde causes tissue injury through genotoxicity, adduct formation and associated immunotoxicity, but its role in causing pancreatitis needs clarification. In the oxidative pathway, in addition to ADH, alcohol may also be metabolized by cytochrome P4502E1 (CYP2E1), which has been shown to be induced in rat pancreas by chronic ethanol administration. Alcohol's metabolism by CYP2E1 results in the generation of reactive oxygen species (ROS), which may initiate tissue injury via activation of nuclear factor kappaB (NF-kB) and increased transcription of proinflammatory cytokines. Fatty acid ethyl esters have been shown to increase the fragility of pancreatic lysosomes which may release hydrolases capable of activating trypsinogen within the pancreas, thereby predisposing the pancreas to autodigestive injury. Additional studies are required to understand the relative role of oxidative and non-oxidative metabolism in ethanol-induced pancreatic injury. One of the major features of chronic alcoholic pancreatitis is fibrosis resulting from increased production of extracellular matrix proteins, including collagen, by activated pancreatic stellate cells (PSCs). Although several factors such as acetaldehyde, oxidative stress, and cytokines have been implicated in mediating alcohol's effect on PSCs activation, the underlying molecular mechanisms need to be elucidated. In addition to direct effects of alcohol, various factors such as substance abuse, genetic makeup, bacterial and viral infection, smoking, high fat diet, compromised immune function, gallstones, and drinking patterns may render the pancreas more susceptible to alcohol- induced tissue injury. Mechanisms underlying the interactive effects of alcohol and these predisposing factors need to be elucidated. Research Scope: Appropriate topics for investigation under this PA would include, but are not limited to: o Elucidation of mechanisms by which alcohol induces or promotes premature activation of pancreatic enzymes (zymogens) within the pancreas directly or indirectly. o Characterization of the interactive effects of alcohol and cholecystokinin on the initiation and perpetuation of alcoholic pancreatitis. o Determination of the role of diet, including fat and protein, in the modulation of gene expression and synthesis of various secretagogues. o Investigation of the role of acetaldehyde and fatty acid ethyl esters in the initiation and progression of alcoholic pancreatitis. o Determination of the role of oxidative stress in the activation of transcription factors that are involved in regulating proinflammatory cytokines. o Determination of the roles of cytokines, chemokines, adhesion molecules, and inflammatory leukocytes in the initiation and progression of inflammation of the pancreas. o Investigation of the role of gut-derived endotoxin in triggering the process of inflammation through activation of pancreatic acinar cells and inflammatory leukocytes. o Characterization of the molecular mechanisms of pancreatic stellate cell activation leading to increased deposition of extracellular matrix proteins and fibrosis. o Investigation of the role of impaired immune function in rendering the pancreas more susceptible to the injurious effect of alcohol. o Determination of the influence of drinking patterns on the pathogenesis of the disease. o Investigation of the role of other factors such as substance abuse, smoking, bacterial and viral infection, gallstones, and genetic susceptibility in the initiation and progression of alcoholic pancreatitis. o Determination of the influence of gender and ethnicity on the course of alcoholic pancreatitis. o Characterization of the relationship between pancreatitis, diabetes, obesity, and pancreatic cancer. o Identification and characterization of biomarkers of early cell or tissue perturbation that can be used for diagnosis of the disease. o Study of pharmacology of drug-induced pancreatitis including that caused by non-nucleotide and protease inhibitor anti-retroviral therapeutic agents. MECHANISM(S) OF SUPPORT This PA will use the NIH R01 and Exploratory/Developmental Research Grant (R21) award mechanisms (http://grants1.nih.gov/grants/guide/pa-files/PA-03-107.html). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Applications using the R21 mechanism may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (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. Otherwise follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Exploratory/developmental grant support is for new projects only; competing continuation applications will not be accepted. Two revisions of a previously reviewed exploratory/developmental grant application may be submitted as defined in NIH Policy at http://grants.nih.gov/grants/policy/amendedapps.htm. 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 institutions/organizations 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 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 Biomedical Research Branch Division of Basic Research National Institute on Alcohol Abuse and Alcoholism National Institutes of Health 6000 Executive Boulevard/ suite 402 Bethesda, M.D., 20892-7003 (for courier service use Rockville, MD 20852) Phone: (301) 443-2689 Fax: (301) 594-0673 Email: vpurohit@niaaa.nih.gov Jose Serrano M.D., Ph.D. Director Liver & Biliary Programs Liver Disease Research Branch Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 657, MSC 5450 Bethesda, M.D., 20892-5450 (for courier service use 6707 Democracy Blvd, Room 657, Bethesda, M.D., 20817) Phone: (301) 594-8871 Fax: (301) 480-8300 Email: js362q@nih.gov Jag H. Khalsa, Ph.D. Pharmacologist/Health Scientist Administrator Center on AIDS & Other Medical Consequences of Drug Abuse (CAMCODA) National Institute on Drug Abuse, NIH 6001 Executive Blvd., Room 5098, MSC 9593 Bethesda, M.D., 20892-5953 (for courier service use Rockville, MD 20852) Phone: (301) 443-1801, (301) 443-2159 (direct) Fax: (301) 480-4544, or (301) 594-6566 e-mail: jk98p@nih.gov o Direct your questions about financial or grants management matters to: Judy Fox (formerly Simons) Chief, Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504 Bethesda, MD 20892-7003 (for courier service use Rockville, MD 20852) Telephone: (301) 443-4704 Fax: (301) 443-3891 Email: jsimons@willco.niaaa.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B;) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. 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. The title and number of this PA must be typed on line 2 of the face page of the application. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://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 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. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must contact the proper program official identified above to receive authorization to submit the proposal. The applicant must include a cover letter identifying the NIAAA program official 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 http://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 mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups 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 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 written critique 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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 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? 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 "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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://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, in the project description and elsewhere in the application as appropriate, 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 http://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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm 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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Department of Health and Human Services |
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National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |