ALCOHOLIC HEPATITIS: CELLULAR AND MOLECULAR MECHANISMS

RELEASE DATE:  March 14, 2002

PA NUMBER:  PA-02-078

EXPIRATION DATE: March 15, 2005, unless reissued.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
 (http://www.niaaa.nih.gov/)
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the 
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)  
seek grant applications to study the underlying cellular, biochemical, 
and molecular mechanisms by which chronic ethanol ingestion leads to 
the initiation and development of alcoholic hepatitis. Left untreated, 
this condition could further progress to hepatic cirrhosis, which is a 
major cause of death in this country. Chronic hepatitis C infection 
(1.8% of the US population) along with the alarming increases in 
overweight and obesity across all ages, racial and ethnic groups, and 
both genders (61% adults and 13% children) are significant causes of 
liver morbidity. The institutes are also interested in research that 
elucidates interactions between alcohol and either HCV infection, 
obesity, or nutritional deficiencies which can potentiate the severity, 
and accelerate the course of alcoholic hepatitis. Understanding the 
mechanisms may help to design strategies for the effective prevention 
and treatment of the disease.  

RESEARCH OBJECTIVES

Alcoholic liver disease (ALD) is a major cause of illness and death in 
the USA. It is the fourth leading cause of death among adult men of 24-
65 years residing in urban areas. Women are more susceptible to 
alcohol-induced liver damage than men and develop alcoholic liver 
disease at a more rapid rate having imbibed less alcohol. This disease 
is characterized by fatty liver, hepatitis, fibrosis, and cirrhosis. 
Cirrhosis is the eleventh leading cause of death in this country. 
Approximately 50% of all deaths due to liver cirrhosis involve alcohol 
abuse and alcoholism. Up to 35 percent of heavy drinkers develop 
alcoholic hepatitis, though the condition is often unrecognized and 
poorly diagnosed. The clinical features of alcoholic hepatitis may 
include abdominal pain, fever, jaundice, and liver failure.  The 
disease can progress to cirrhosis and even hepatocellular carcinoma. 
Histopathologically, it is characterized by liver cell death and 
infiltration of leukocytes into the hepatic parenchyma. Although many 
treatments are being used for the amelioration of alcoholic hepatitis, 
none of them are effective. To develop an effective treatment for this 
disease, it is important to understand the underlying mechanisms by 
which chronic alcohol ingestion triggers the development of the 
inflammatory disease process. 

Researchers have made significant progress in understanding the 
mechanisms of alcohol-induced early liver injury. Alcohol is thought to 
render the intestinal wall more permeable to endotoxin. This results in 
increased amount of bacterial endotoxin in hepatic portal system, which 
activates Kupffer cells of the liver via the CD14 surface receptor. 
This activation initiates a cascade of events leading to increased 
generation of free radicals, activation of nuclear transcription 
factor-kB (NF-kB), increased transcription of inflammatory cytokines 
and chemokines, increased expression of adhesion molecules, and 
increased infiltration of inflammatory cells into the liver. These 
changes are associated with the histopathological findings of fatty 
liver, patchy necrosis, and mild inflammation of the liver. Despite 
this progress in our understanding of ALD, the mechanisms by which 
chronic ethanol consumption results in alcoholic hepatitis in humans 
are not clear. This Program Announcement addresses the following 
issues: 1) role of Kupffer cells in triggering the process of 
inflammation; 2) types of leukocytes that are involved in the 
pathogenesis of alcoholic hepatitis; 3) the chemokines that are 
responsible for the attraction of leukocytes into the liver; 4) the 
adhesion molecules that promote the attachment of leukocytes to 
endothelial cells and hepatocytes; 5) the mechanisms of leukocyte 
transmigration into the hepatic parenchyma; 6) the mechanisms by which 
leukocytes initiate tissue injury (free radicals vs. proteases); 7)the 
mechanisms of interactive effects of alcohol, HCV, and HIV on the 
progression of hepatitis; 8)interaction between alcohol and 
overweight/obesity; 9) the role of nutrient deficiencies; and 10) 
potential targets of interventions for the disease.    

Appropriate topics for investigation under this PA would include, but 
are not limited to:

o Investigation of the mechanisms by which Kupffer cell-generated 
inflammatory mediators injure endothelial cells and hepatocytes, and 
stimulate migration of leukocytes into hepatic parenchyma.

o Elucidation of the mechanisms by which neutrophils, monocytes and 
lymphocytes are activated in hepatic sinusoids, attach to endothelial 
cells, and pass through the cell lining into the hepatic parenchyma. 

o Determination of the types and cellular sources of chemokines and 
adhesion molecules involved in attracting leukocytes and their 
attachments at different stages of inflammation. Can blocking the 
synthesis of chemokines and adhesion molecules arrest the inflammatory 
process?

o Exploration of the mechanisms of peripheral blood mononuclear cell 
activation in response to chronic ethanol ingestion. 

o Determination of which cell type neutrophil, monocyte or lymphocyte 
initiates damage to hepatocytes. Do these cells interact in a 
coordinated fashion to damage hepatocytes? 

o Investigation of how neutrophils, monocytes and lymphocytes attach to 
hepatocytes and injure or kill these cells directly.  

o Determination of the subsets of neutrophils, monocytes and 
lymphocytes whose function may be compromised by ethanol, making the 
liver more susceptible to injury by alcohol. 

o Elucidation of the internal cellular mechanism(s)hepatocytes may use 
to cause self-injury. 

o Investigation of whether hepatocyte injury is mediated through 
increased ethanol metabolism-associated oxidant stress, cytokine-
induced cell death, or chemokine-induced recruitment of inflammatory 
cells. 

o Determination of how alcohol intake increases the severity of HCV-
induced liver injury. Investigation of alcohol's effect on promoting 
viral replication, or inhibiting viral clearance is encouraged. 

o Determination of the impact of HIV infection on the pathogenesis of 
alcoholic hepatitis.

o Investigation of the role of nutrient deficiencies in the 
pathogenesis of alcoholic liver injury, and on the tissue injury repair 
process.

o Study the interaction between alcohol and obesity on the progression 
from injury to repair in hepatocytes. 

o Characterization of biomarkers that can be used for early diagnosis 
of alcoholic hepatitis.

o Identify and test potential targets of interventions for the disease, 
such as inhibition of alcohol-inducible enzymatic activity (i.e CYP2E1) 
involved in the generation of free radicals, as well as new anti-
inflammatory and antiviral drugs.       

MECHANISM(S) OF SUPPORT 

This PA will use the NIH research project grant (R01) small grant (R03) 
and Exploratory/developmental grant (R21) award mechanism.  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. The total project period for a research 
project grant (R01) application submitted in response to this Program 
Announcement may not exceed 5 years.  Exploratory/developmental grants 
(R21) are limited to 3 years for up to $100,000/year for direct costs. 
(See Program Announcement PA-99-131, "NIAAA Exploratory/Developmental 
Grant Program," http://grants.nih.gov/grants/guide/pa-files/PA-99-
131.html, for a complete description of the R21 mechanism.)    

Under the NIAAA Small Grant mechanism (R03) applicants may request 
either $25,000 or $50,000 in direct costs per year for up to two years.  
These awards are not renewable; however, a no-cost extension
of up to one year may be granted to the grantee institution prior to 
expiration of the project period. Before completion of the R03, 
investigators are encouraged to seek continuing support for research 
through a research project grant (R01).  (See Program Announcement PA-
99-098, "NIAAA Small Grant Program," 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, for a 
complete description of the R03 mechanism.)

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs. 

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the 
opportunity to answer questions from potential applicants. Inquiries 
may fall into two areas: scientific/research, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Vishnudutt Purohit, Ph.D.
Program Director
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD  20892-7003 (for express mail, use Rockville, MD  20852)
Telephone: (301) 443-2689	
FAX: (301) 594-0673
Email: vpurohit@willco.niaaa.nih.gov

Jose Serrano M.D., Ph.D.
Director
Liver & Biliary and Pancreas Programs
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 657, MSC 5450
BETHESDA MD 20892-5450 (For Courier service use: 6707 Democracy Blvd, 
Room 657 BETHESDA MD 20817)
Telephone: (301) 594-8871 
FAX: (301) 480-8300
Email: SerranoJ@extra.niddk.nih.gov

o Direct your questions about financial or grants management matters 
to:

Judy Fox Simons
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 505
6000 executive Blvd. (MSC-7003)
Bethesda, MD 20892-7003 (for express mail, use Rockville, MD 20852)
Telephone: (301) 443-4704
Email: jsimons@willco.niaaa.nih.gov

Donita Marconi
Grants Management Specialist
National Institute of Diabetes, Digestive and Kidney Diseases
Two Democracy Plaza, Room 710
Bethesda, MD 20892-5456 (for express mail, use Rockville, MD 20852)
Telephone: (301) 594-8860
Email: Marconid@extra.niddk.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format. For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at 
http://grants.nih.gov/grants/dates.htm. Application deadlines are also 
indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format. The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail. Applicants request direct costs in $25,000 
modules. Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR:  Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of NIH institutes or centers who has agreed to accept 
assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five signed 
photocopies in one package 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)

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.  The CSR 
will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept 
any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
score
o 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 comments, reviewers will be asked to discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well-suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

DATA SHARING: The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available 
funds with all other recommended applications. The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy 
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health of 
the subjects or the purpose of the research. This policy results from 
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20
01.htm.  The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem 
Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).  It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This PA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.273 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284)and administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.


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