Full Text PA-96-079
 
ONTOGENY AND DIFFERENTIATION OF THE LIVER AND BILIARY TREE
 
NIH GUIDE, Volume 25, Number 33, October 4, 1996
 
PA NUMBER:  PA-96-079
 
P.T. 34

Keywords: 
  Biology, Cellular 
  Morphogenesis 

 
National Institute of Diabetes and Digestive and Kidney Diseases
 
PURPOSE
 
This initiative encourages research applications in the
identification and characterization of the cellular lineages of the
liver and biliary tree.  Substantial evidence has accumulated
indicating the existence of stem cells in the liver.  In ontogeny,
hepatoblasts have the ability to differentiate into hepatocytes and
biliary cells.  As the organ develops, cellular terminal
differentiation occurs and there appears to be an inverse
relationship between cellular differentiation and cell proliferation.
However, the liver is a unique organ in the capacity to regenerate
subsequent to specific forms of trauma, such as partial hepatectomy.
It is unclear the quantity and form of hepatic progenitor cells which
could exhibit unique characteristics promoting novel therapeutic
approaches in, for example, hepatocyte transplantation, gene therapy
and artificial liver assist devices.  Thus, the identification and
characterization of hepatic progenitor stem cells could have a
substantial impact on current experimental therapies for human liver
disease.
 
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,
Ontogeny and Differentiation of the Liver and Biliary Tree, 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), the FIRST (R29) award, and the small
grants (R03) award.  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, Vol. 25, No.10, March 29, 1996.  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 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
 
This initiative encourages research applications in the
identification and characterization of the cellular lineages of the
liver and biliary tree.  Substantial evidence has accumulated
indicating the existence of stem cells in the liver.  In ontogeny,
hepatoblasts have the ability to differentiate into hepatocytes and
biliary cells.  As the organ develops, cellular terminal
differentiation occurs and there appears to be an inverse
relationship between cellular differentiation and cell proliferation.
However, the liver is a unique organ in the capacity to regenerate
subsequent to specific forms of trauma, such as partial hepatectomy.
It is unclear the quantity and form of hepatic progenitor cells which
could exhibit unique characteristics promoting novel therapeutic
approaches in, for example, hepatocyte transplantation, gene therapy
and artificial liver assist devices.  Thus, the identification and
characterization of hepatic progenitor stem cells could have a
substantial impact on current experimental therapies for human liver
disease.
 
This program announcement specifically requests applications that
will advance the current knowledge of hepatocyte cloning, long term
cell culture, cellular differentiation and characterization as well
as provide novel hypotheses for the elucidation of hepatocyte and
biliary cell differentiation in the following areas:
 
o  hepatic cell transplantation
o  hepatic regeneration
o  hepatic gene therapy
o  susceptibility of cellular populations to viral infection
o  artificial liver assist devices
o  cellular participation in the induction of hepatic pathology
o  cellular signal transduction and transport
o  cellular apoptosis
 
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.
 
Mail the original, single-sided application, along with five exact,
single-sided copies and five collated sets of appendix materials (if
included) 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, 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 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.  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
 
Direct inquiries regarding fiscal and administrative matters to:
 
Sharon Bourque
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, 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 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.
 
.

Return to PA Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.