Full Text PA-96-045 ETIOLOGY OF BILIARY ATRESIA AND OTHER PEDIATRIC CHOLESTATIC LIVER DISEASES NIH GUIDE, Volume 25, Number 13, April 26, 1996 PA NUMBER: PA-96-045 P.T. 34 Keywords: Digestive Diseases & Disorders Etiology National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development PURPOSE The Division of Digestive Diseases and Nutrition of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Center for Research for Mothers and Children of the National Institute of Child Health and Human Development wish to encourage research in the various clinical forms of neonatal cholestasis with an emphasis on the idiopathic obstructive cholangiopathies, extrahepatic biliary atresia and idiopathic neonatal hepatitis as well as toxic or drug-related biliary stasis associated with total parenteral nutrition. Research strategies for biliary atresia or neonatal hepatitis can be devised based on the paucity of information regarding (1) the etiology of disease, as either a single phenotype or with multiple primary etiologies; (2) predictors of natural history and risk factors; or (3) optimal use and timing of medical intervention versus surgical intervention. Applications that focus on the viral etiology of idiopathic neonatal hepatitis will be accepted as unsolicited applications, but will not be considered responsive to this program announcement. Research strategies for biliary stasis associated with total parenteral nutrition can be devised on studies of the etiology and control of the liver damage in hyeralimentation. Thus, research applications are sought that develop novel hypotheses and assess their application to the pathogenesis and therapy of these diseases. This program announcement is primarily designated for research on human subjects, although animal models may be developed to establish or confirm specific hypotheses. 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, Etiology of Pediatric Cholestatic Liver Disease, 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 nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) (R29) awards. 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) award, the FIRST (R29) award, and the small grants (R03) award. The research project grant award (R01) is the investigator initiated grant-in-aid. First Independent Research Support and Transition (FIRST) (R29) award applicants must adhere to the R29 Administrative Guidelines (revised February, 1994) for eligibility, budget and period of award. Potential R29 applicants should refer to the announcement on "Just-in-Time Procedures for FIRST and Career Awards" (NIH Guide for Grants and Contracts, Vol. 25, No.10.) 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. Applicants will be responsible for the planning, direction, and execution of the proposed project. 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 Neonatal liver disease is an uncommon but important cause of morbidity and mortality in children. The syndrome known as "neonatal cholestasis" occurs in approximately one in 10,000 newborns. It represents not just one disease but several, the most common of which are biliary atresia and idiopathic neonatal hepatitis (also known as giant-cell hepatitis). Biliary atresia is a very serious condition that leads to end-stage liver disease within 6 to 18 months after birth. Early surgery using the porto-enterostomy (the Kasai procedure) can halt the progression of the liver disease; however, this surgery must be done within 90 days of birth, and even when successfully performed may not completely halt eventual progression to cirrhosis and resulting disability from liver disease. As a consequence, biliary atresia is the major reason for liver transplantation in children and accounts for approximately 13% of all liver transplantation done in the U.S. Children undergoing liver transplants for biliary atresia usually do well, the transplant reversing the severe liver failure. However, these children must then lead their entire lives with a foreign graft, requiring profound, life-long immunosuppressive therapy. The cause of biliary atresia is unclear; it is most likely congenital but not genetic or inherited. There are few hypotheses concerning its etiology, cause, treatment or prevention. Understanding and controlling biliary atresia is a major challenge to the biomedical research community. Another major cause of neonatal cholestasis is idiopathic neonatal hepatitis. As the name implies, the cause of this syndrome is unknown. It is usually self-limited, although the newborn can be ill with it for many months. There is controversial evidence for the role of infection in this condition. Thus, there are major needs for means of diagnosis and management of neonatal hepatitis. The important differential diagnosis is biliary atresia, but identification of this disease is also important for early and appropriate management. A condition that is at least as common as biliary atresia, although usually less serious, is biliary stasis and liver damage resulting from prolonged parenteral nutrition of very low birth weight infants and infants with disorders of the gastrointestinal tract. Although the feasibility of total parenteral nutrition has resulted in a better prognosis for gatrointestinally impaired infants with intestinal anomalies, surgical resections or necrotizing enterocolitis, this life-saving therapy is often accompanied by the risk of cholestasis. The cholestasis of these infants is first manifested by mild direct hyperbilirubinemia, superimposed on the normally transient hepatocyte dysfunction of newborns. There is biopsy evidence of hepatocellular injury, with swelling of hepatocytes, necrosis, and occasional giant cell transformation. Maintenance of parenteral nutrition in the presence of the cholestasis may cause progression to cirrhosis. The etiology of the pathological cholestasis in parenterally-fed neonates is uncertain. It has been variously ascribed to the dextrose content of the fluid or to the competition of infused amino acids for the bile acid hepatocellular re-uptake. A minority of cases may be due to bile sludging in the gall bladder with secondary obstruction in the common bile duct. The lack of enteral feeding may contribute by decreasing the secretion of normal bile flow-stimulating gut hormones. The aim of this program announcement is to promote research support and guidance for identifying the causes, means of treatment and prevention of biliary atresia and neonatal hepatitis as well as the etiology and control of the liver damage in hyperalimentation. Specifically, applications are sought that provide novel hypotheses for these diseases that could include, but not be limited to: o biliary atresia as a defect of visceral laterality with the identification of the genetic basis for the organ orientation during embryogenesis; o biliary atresia as a developmental defect in expression of a hepatocyte growth factor or oncogene; o HLA-associations and biliary atresia; o viral etiology of biliary atresia; o biliary atresia as a result of maternal exposure to environmental toxins or infectious agents; o amelioration of hepatic injury with bile acids or antioxidants; o early clinical differential diagnosis with identification of definitive noninvasive diagnostic tests; o role of fibrogenic growth factor, cytokines and adhesion molecules in the progressive hepatic fibrosis; o ontogeny of hepatocytes, cholangiocytes and epithelial cell lineages; o bile acid metabolism and bile acid flow in neonates; o immunopathogenesis of neonatal immune-mediated bile duct injury, hepatocellular necrosis and apoptosis; o maternal-fetal transfer of cholestatic liver disease; o etiology and control of liver damage in hyperalimentation; o outcome studies detailing the optimum use of medical and surgical interventions. Applications that focus on the viral etiology of idiopathic neonatal hepatitis will be accepted as unsolicited applications, but will not be considered responsive to this program announcement. 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) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 20, 1994 (FR 59 14508-14513) and reprinted 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. 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, or may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: asknih@odrockm1.od.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. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS 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 Public Health Service 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 o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups 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, the safety of the research environment. For Applications from Foreign Organizations: o availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. 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 Ephraim Y. Levin, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development Building 61E, Room 4B11 Bethesda, MD 20892 Telephone: (301) 496-5593 FAX: (301) 402-2085 Email: fjt@cu.nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Sharon Bourque Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8846 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 routing 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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