PREVENTION OF END STAGE LIVER DISEASES BY MOLECULAR DIAGNOSIS NIH GUIDE, Volume 21, Number 35, October 2, 1992 PA NUMBER: PA-93-002 P.T. 34 Keywords: Diagnosis, Medical Biology, Molecular Genetics National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The purpose of this Program Announcement (PA) is to encourage research on isolating the gene(s) or the full length cDNAs for the gene(s) of the many genetic liver diseases in which early diagnosis and treatment could avert progressive serious liver injury. Liver transplantation is often the only treatment for these diseases when they are not detected and treated early. Two of the liver diseases in which early diagnosis could be curative and in which much information exists about the gene and/or its location are Wilson's disease and hemochromatosis. 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, Prevention of End Stage Liver Diseases by Molecular diagnosis, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit United States organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) Awards (R29). MECHANISM OF SUPPORT The Research Project Grant (R01), the FIRST Award (R29), and the Interactive Research Project Grant (interactive R01s) are all appropriate mechanisms. Program Project Grant (P01) or Center Grant (P30) applications will not be accepted. RESEARCH OBJECTIVES Hemochromatosis and Wilson's disease are two inherited diseases of trace metal metabolism that can cause end stage liver disease. If diagnosed early before the onset of significant liver damage, available treatments are usually effective. Unfortunately, both hemochromatosis and Wilson's disease are rarely diagnosed before the onset of symptoms in the liver or other organs. Both diseases result in liver cirrhosis for which liver transplantation is the only effective treatment. Currently, there is no easy means of early screening for either disease since the genetic defect has not been positively identified. Hemochromatosis, which affects approximately one in 300 persons, appears to be due to an excessive absorption of dietary iron that leads over years to excessive bodily iron stores that eventually cause cellular damage and organ injury in liver, heart, pancreas and gonads. If hemochromatosis is diagnosed, the organ injuries can be averted by phlebotomy to decrease the body iron stores to normal. The enzyme or transport protein responsible for the excessive absorption of iron has not been identified. It is not ferritin, transferrin, or the transferrin receptor. The new techniques of molecular biology promise to provide means of identifying the defect in hemochromatosis. The molecular techniques needed are probably not the conventional ones that proceed from the abnormal protein to the gene, but rather "reverse genetics" that first identifies the gene and from it the abnormal protein. Such techniques were successful in identifying the abnormality in cystic fibrosis and neurofibromatosis. Indeed, in hemochromatosis an advantage has been established already by the known linkage of this disorder with the HLA region on the short arm of chromosome 6. If the gene for hemochromatosis could be identified, genetic screening of newborns could be used to identify homozygotes and to initiate lifelong phlebotomy therapy before the onset of disease or organ damage. Wilson's disease, which affects approximately one in 10,000 persons, appears to be due to a genetic defect in the secretion of copper in bile that leads over time to a gradual accumulation of excessive copper stores in the liver, red blood cells, synovium, kidneys and brain. Untreated Wilson's disease leads to irreversible end stage liver disease and/or brain damage between the ages of 15 and 40 years. If Wilson's disease can be identified early, however, the copper accumulation can be prevented by chelation therapy (d-penicillamine) and the liver and brain disease completely averted. Unfortunately, Wilson's disease is rarely diagnosed early, and this is still an important cause of liver failure necessitating liver transplantation. Approaches that might be taken to identify the Wilson's disease gene also include those of reverse genetics by identifying genetic markers that co-segregate with this disease. Such studies require data collected from large families with Wilson's disease using multiple genetic markers. These studies have shown that this gene is located on chromosome 3. Further studies are needed to more closely locate the gene to a fragment of DNA that can be sequenced and characterized. Both of these examples of diseases that could benefit from appropriate early diagnosis through molecular biology techniques require the availability of large family cohorts to serve as subjects and controls. The availability of multi-generational families in which linkage analyses can be done will be very important to progress in these studies. Other liver diseases such as Alagille syndrome and Crigler-Najjar syndrome type I, in which early diagnosis may make available treatment(s) that can prevent serious liver malfunction, may also be submitted and be responsive to this PA. The emphasis in this announcement is on the diagnosis of the genetic defect and not on the treatment of the disease. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS It is NIH policy that women and minorities must be included in clinical study populations unless there is a good reason to exclude them, and the study design must seek to identify any pertinent gender or minority population differences. NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, the NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups must be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to the NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the regular application deadlines as indicated in the application kit. FIRST (R29) Award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award applications submitted without the required number of reference letters will be considered incomplete and will be returned to the applicant without review. Application kits are available at most institutional business and grant/contract offices and may be obtained from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/496- 7447. The title and number of this announcement must be typed in Section 2a on the face page of the application. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned to initial review groups and to Institutes or Centers for possible funding on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by initial review groups of the Division of Research Grants in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by an appropriate National Advisory Council. 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 balance among research areas of the announcement INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Sarah C. Kalser, Ph.D. Liver and Biliary Diseases Program Director Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 5333 Westbard Avenue, Room 3A-05 Bethesda, MD 20892 Telephone: (301) 496-7858 David G. Badman, Ph.D. Hematology Program Director Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 5333 Westbard Avenue, Room 3A-05 Bethesda, MD 20892 Telephone: (301) 496-7458 Direct inquiries regarding fiscal matters to: Miss Aretina Perry Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, MD 20892 Telephone: (301) 496-7467 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. .
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