This Program Announcement expires on July 1, 2004, unless reissued. LIVER AND PANCREATIC DISEASE IN HIV INFECTION Release Date: July 17, 2001 PA NUMBER: PA-01-117 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.pdf. PURPOSE The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID) invite clinical and basic research applications that focus on the pathogenesis and therapeutics of the liver and pancreatic disease associated with coinfections that occur in patients with HIV infection or the metabolic complications associated with treatment of HIV infection. The coinfections targeted by this Program Announcement (PA) specifically include hepatitis B and hepatitis C, which are frequent causes of end-stage liver disease, a leading cause of death in HIV infected patients. Metabolic complications, involving the liver and pancreas, associated with the treatment of HIV infection include: hepatic drug toxicity, hepatic lipid metabolism, nonalcoholic steatohepatitis (NASH) and pancreatitis, which are all important causes of morbidity in patients with HIV infection. The proposed studies should advance our understanding of the pathogenesis of liver and pancreatic disease in patients with HIV and/or metabolic complications of therapy. These advances should lead to enhanced medical management of individuals infected with HIV. 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 Program Announcement (PA), Title of 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/. 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. 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) as well as the Exploratory/Developmental Grant (R21) award 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 in response to this PA may not exceed five years. Applicants for the R21 grant mechanisms may request up to $ 150,000 direct costs per year and support may not exceed two years. This mechanism provides short duration support for preliminary studies of a highly speculative nature, which are expected to yield sufficient information upon which to base a well- planned and rigorous series of further investigations. The R21 grants are non- renewable and competing continuation of projects developed under this grant mechanism will be through the R01 research grant mechanism. Funds and time requested should be appropriate for the research proposed. RESEARCH OBJECTIVES Background The current initiative specifically targets hepatic and pancreatic comorbidities in the context of HIV infection, and metabolic complications of antiretroviral treatment in support of basic and clinical research that addresses the significant emerging clinical issues of disease progression in patients with HIV infection. Highly active antiretroviral therapy (HAART) has slowed the progression of HIV disease and decreased the rate of HIV-associated mortality. In the context of enhanced longevity for HIV patients, other comorbidities, such as chronic liver disease and pancreatitis, can assume greater importance in the medical management of patients. Based on shared routes of transmission, HBV and HCV infection are common in HIV-infected patients. HIV infection has a significant effect on the natural history of HBV infection with coinfected individuals more likely experience severe liver disease. Individuals treated with lamivudine as part of their antiretroviral treatment more frequently fail treatment, resulting in the emergence of drug resistant strains of HBV. Several studies have also documented that HIV diseases modifies the natural history of chronic HCV infection leading to an accelerated course of progression to end-stage liver disease and death. The accelerated course to end-stage liver disease has been suggested to be reduced from the 2-4 decade time-frame for HCV mono-infection to as little as 5-6 years in HCV/HIV coinfected patients. The result of the common occurrence of hepatitis and HIV coinfection and accelerated disease progression is the report that end-stage liver disease is now the leading cause of death in hospitalized HIV-infected patients. The etiology and pathogenesis of enhanced progression to end-stage liver disease in HIV coinfected patients is unknown. Recent data have shown that hepatitis coinfection results in enhanced liver disease in individuals infected with HIV through enhanced severity of fibrosis, a higher frequency of cirrhosis and end-stage liver disease as well as increased deaths due to liver disease. The role of HCV quasispecies, the effects of immune deficiency on the course of hepatitis C, hepatotoxicity due to antiretroviral treatment, chronic HBV infection, immune restoration and HBV infection, and development of nonalcoholic steatohepatitis (NASH) as a result of lipodystrophy have all been hypothesized to play a role in the enhanced liver disease seen in co-infected individuals. Additional research is need to identify the mechanism(s) of pathogenesis and to identify therapeutic targets for treatment. This initiative will support basic and clinical research in HIV co-infection and metabolic disease related to antiretroviral treatment. Areas of interest include but are not limited to: o The elucidation of biological mechanism(s) that promote enhanced progression of liver disease in HIV-infected patients; o A further elucidation of drug-induced hepatotoxicity associated with anti-retroviral treatment regimens; o The identification of therapeutic targets and/or novel therapies for the treatment of liver disease in HIV-infected patients; o The elucidation of synergy between HIV and HCV, resulting in enhanced liver disease; o Enhanced knowledge of antiviral treatment failures of HBV/HIV coinfection and the emergence of HBV drug-resistant strains; o Identify underlying liver disease, such as NASH, in combination with HIV infection and antiretroviral treatment, that progresses to end-stage liver disease; o Therapeutics development for the enhanced medical management of patients with HBV/HIV or HCV/HIV coinfection or metabolic abnormalities due to antiretroviral treatment; o Altered hepatic lipid metabolism due to antiretroviral treatment; o HIV-associated pancreatitis and risk factors- hypertriglyceridemia, obesity and gallstones; o The impact of liver transplantation on disease progression in select patients with co-infections with Hepatitis B or Hepatitis C. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: 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. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in applying for these grants. This version of PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html All application instructions outlined in the PHS 398 application kit are to be followed, with the following modifications for R21 applications: 1. R21 applications will use the MODULAR GRANT and JUST-IN-TIME concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $150,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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 will be evaluated for scientific and technical merit by an appropriate scientific 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. 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 recommended applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o availability of funds o program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Frank Hamilton, M.D., M.P.H. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Building, Room Number Bethesda, MD 20892 Telephone: (301) 594-8877 FAX: 301 480-8300 Email: fh14e@nih.gov Thomas Kresina, Ph.D. Therapeutics Research Program Division of AIDS National Institute of Allergy and Infectious Diseases 670OB Rockledge Drive , Room 5229 Bethesda, MARYLAND 20892-7624 Telephone ( 301( 435-3762 FAX 301 (301) 402-3171 Email: tk13@nih.gov Direct inquiries regarding fiscal matters to: Ms. Donita Marconi Grants Management Branch , Division of Extramural Activities National Institute of Diabetes, Digestive , and Kidney Diseases Democracy 2, 6707 Democracy Boulevard , Room 710 Bethesda, MD 20892- 5450 Telephone: (301) 594-8860 FAX: (301) 480-3504 Email: dm150h@nih.gov Ms. Linda Shaw Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2125 6700 B Rockledge Drive MSC 7614 Bethesda, MD 20892-7614 Telephone : (301) 402- 6611 FAX: (301) 480-3780 Email: ls15k@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.856- Microbiology and Infectious Diseases Research, No. 93.855-Immunology, Allergy, and Transplantation Research, No. 93.121-Oral Diseases and Disorders Research. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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