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 investigatorþinitiated 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 301-435-0714, 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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