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
301/435-0714, 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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