PA-98-086: LIVER AND BILIARY DISEASES AMONG WOMEN AND MINORITIES

Department of Health
and Human Services (HHS)

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LIVER AND BILIARY DISEASES AMONG WOMEN AND MINORITIES Release Date: June 30, 1998 PA NUMBER: PA-98-086 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse Office of Research on Minority Health Office of Research on Women"s Health PURPOSE Some liver diseases occur only in women and others are more frequent in women than men. Specific to women are the liver diseases of pregnancy such as acute fatty liver of pregnancy, cholestasis of pregnancy and liver disease associated with pre-eclampsia, hepatic infarction and rupture. Liver and biliary diseases that affect both sexes but are more frequent in women include hepatic adenomas, gallstones, primary biliary cirrhosis, autoimmune liver diseases and non- alcoholic steato-hepatitis (NASH). Also, management of liver disease may present specific problems in women, for instance the influence of estrogen replacement therapy on the natural history of liver disease and the management of osteoporosis in women with liver disease and abuse of illicit drugs. Addressing these issues is critical for the optimal clinical management of liver disease in women. Several liver and biliary diseases are more common or more severe among minority individuals reflecting both cultural and socioeconomic factors. These conditions include chronic hepatitis C among African Americans and Hispanics, alcoholic and drug abuse liver disease among Native and African Americans and gallstones and gallbladder cancer among Mexican Americans and Native Americans. Although liver disease mortality is higher among minorities, liver transplantation rates and both patient and graft survival after liver transplantation are lower than among non-Hispanic whites. Although liver disease mortality is higher among minorities, liver transplantation rates and both patient and graft survival after liver transplantation are lower than among non-Hispanic whites. The reasons for these differences are unknown, ethnicity and confounding factors including socio- economic, environmental, and behavioral factors, such as injection drug use and less access to health care are rarely evaluated in assessing therapies for liver and biliary disease. Thus, this Program Announcement requests applications from experienced and new investigators who will pursue basic and clinical investigations that will address liver and biliary diseases in women and underrepresented minorities. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Liver and Biliary Diseases Among Women and Minorities, is related to the priority area of chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). 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 The support for this program announcement will be through the NIH research project grant (R01) and the small grants award (R03). The small grants research program (R03) provides limited funds (maximum of $50,000 direct costs per year) for short term (up to two years) research projects. These grants are non- renewable, but continuation of projects developed under this program can be supported by the investigator initiated research project grant (R01) mechanism. Applicant will be responsible for the planning, direction, and execution of the proposed project. Applications submitted in response to this PA will compete for funds with other regular research project grant applications. Applications from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. The award of grants in response to this PA is also contingent upon the availability of funds. Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement (rev. 4/94). RESEARCH OBJECTIVES Summary Women"s Health and Liver and Biliary Disease Some liver diseases occur only in women and others are more frequent in women than men. Specific to women are the liver diseases of pregnancy such as acute fatty liver of pregnancy, cholestasis of pregnancy and liver disease associated with pre-eclampsia, hepatic infarction and rupture. Liver and biliary diseases that affect both sexes but are more frequent in women include hepatic adenomas, gallstones, primary biliary cirrhosis, autoimmune liver diseases and non- alcoholic steato-hepatitis (NASH). Also, management of liver disease may present specific problems in women, for instance the influence of estrogen replacement therapy on the natural history of liver disease and the management of osteoporosis in women with liver disease, and other risk factors such as illicit drug abuse. The role of gender and sex hormones in the pathogenesis of liver and biliary disease is not well known. The nature of liver diseases that are adversely effected by female sex indicate that female sex hormones influence hepatic energy production and utilization, liver cell proliferation, lipid intermediary metabolism, and immunomodulatory responses. In addition, the hepatocyte is rich in receptors for sex-hormones. However, little is known of the effects of the female sex hormones on hepatocellular function and injury or on the susceptibility to or progression of liver disease. Although men account for a higher number of liver cirrhosis cases, women are more susceptible to alcoholic liver disease (ALD) than men. They develop ALD more rapidly than men, and with lesser amount of alcohol intake. Risk for cirrhosis becomes significant with average alcohol intake of 40-60 grams or more per day for men, but with only 20 grams or more for women. Animal studies have also shown that female rats develop fatty liver, inflammation, and necrosis of liver more rapidly and more extensively than male rats after alcohol consumption. The reasons for the increased susceptibility of women to ALD are not known, and further studies are required to understand the mechanisms of gender differences in ALD. Addressing these issues is critical for the optimal clinical management of liver disease in women. Thus, basic (multi-disciplinary), clinical (multi-center) research and clinical trial applications are specifically requested that focus on the following issues in women"s health and liver and biliary disease: o The elucidation of the cause(s) of the liver diseases of pregnancy and the effect of pregnancy on the natural history of pre-existing liver disease such as autoimmune hepatitis, hepatitis C or genetic liver diseases. o The elucidation of the interactions among basic biological mechanisms of liver function and female sex hormones in the context of the development of liver pathogenesis as well as in medical management and therapy of liver disease, such as the use of estrogen replacement therapy in aging women with liver disease. o The elucidation of the effect of female sex on the complications of liver disease such as infertility. o The elucidation of underlying liver pathogenesis in women abusing illicit drugs. o The role of estrogen in the pathogenesis of ALD, and gender differences in the following issues: - Response of Kupffer cells to endotoxin and alcohol in eliciting inflammatory response. - Chemokine release, and neutrophil migration. - Hepatic stellate cell activation and subsequent release of extracellular matrices. - Release of metalloproteinases and degradation of extracellular matrices. Minority Health and Liver and Biliary Disease Several liver and biliary diseases are more common or more severe among minority individuals reflecting both cultural and socioeconomic factors. These conditions include chronic hepatitis C among African Americans and Hispanics, alcoholic and drug abuse liver disease among Native and African Americans and gallstones and gallbladder cancer among Mexican Americans and Native Americans. Although liver disease mortality is higher among minorities, liver transplantation rates and both patient and graft survival after liver transplantation are lower than among non-Hispanic whites. The reasons for these differences are unknown, and race and socio-economic factors and other factors such as the abuse of illicit drugs, are rarely evaluated in assessing either access to or the success of new therapies for liver and biliary disease. Thus, basic (multi-disciplinary), clinical (multi-center) and epidemiological research and clinical trial applications are specifically requested that focus on (but are not limited to) the following issues in minority health and liver and biliary disease: o Define the factors for the differences in prevalence and pattern of liver diseases among different minority groups. For instance, in studies of hepatitis C, analysis of community, cultural, socio-economic, quality of life factors and other environmental factors such as illicit drug abuse are needed in combination with state of the art studies of immunological status, viral strain, quasispecies, and pathogenicity. In studies of therapy, racial and cultural factors need to be analyzed. In studies of alcoholic and/or drug abuse liver disease, the factors of race and socio-economic issues need to be determined. Clinical trials and databases on liver transplantation should include sub- analysis of factors of race and social class. o Develop therapies for end stage liver disease based upon racial and socio- economic factors in susceptibility and response to treatment and prevention. As such, attention to the role of racial and socio-economic differences in all clinical studies and therapeutic trials (for hepatitis B and C, alcoholic liver disease and other abusable hepatoxins) is essential in defining whether these differences are important in patient management and in improving the health of minority individuals. These factors may also play an important role in the exposure to environmental factors such as illicit drug use or liver damaging behaviors that cause liver disease. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.nih.gov/grants/guide/notice-files/not98-024.html. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Mail the signed, original, application, along with five exact, single-sided copies and five collated sets of appendix materials to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. o 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? o 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? o 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? o 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)? o 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? o Appropriateness of the proposed budget and duration in relation to the proposed research. o 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. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with all other approved 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: Thomas F. Kresina, Ph.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8871 FAX: (301) 480-8300 Email: tk13v@nih.gov Vishnudutt Purohit, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20897-7003 Telephone: (301) 443-2689 Email: vp15t@nih.gov Jag H. Khalsa, Ph.D. Clinical Medicine Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-08 Rockville, MD 20857 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: jk98p@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Donita Marconi Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8860 Email: dm150h@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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, 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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