Release Date:  August 23, 1999

PA NUMBER:  PAS-99-155

National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  November 24, 1999
Application Receipt Date:  December 22, 1999; standard receipt dates



The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites basic
and clinical research grant applications that focus on the synergistic
interactions between alcohol consumption and hepatitis C virus (HCV) infection
to produce chronic liver disease.  Heavy alcohol consumption can lead to
alcoholic liver disease and HCV infection can lead to end stage liver disease.
An important unresolved clinical issue in the management of HCV infection is
the level and type of alcohol consumption of patients with HCV.  Several
clinical studies suggest that alcohol intake may be an important cofactor in
the progression of HCV-related liver disease.  However, it is unclear whether
progression to cirrhosis and hepatocellular carcinoma is due to an additive or
a synergistic effect of ethanol and viral infection.  Thus, the underlying
biological mechanism(s) of the development of liver cirrhosis and
hepatocellular carcinoma in individuals who drink alcohol with concurrent HCV
infection remain unknown. This program announcement (PA) solicits both basic
and clinical studies on cellular and molecular mechanisms that initiate and
promote the progression to end stage liver disease in individuals with HCV
infection who consume alcohol. The data generated should provide insight into
novel hypotheses that provide a rational basis for prevention and improved
treatment of patients who abuse alcohol and are infected with HCV.


The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led activity
for setting priority areas.  This PA, Hepatitis C Infection and Alcoholic
Liver Disease, is related to the priority area of alcohol abuse and
alcoholism.  Potential applicants may obtain a copy of "Healthy People 2000"
at http://www.crisny.org/health/us/health7.html.


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


Research support may be obtained through applications for a research project
grant (R01), exploratory/developmental grant (R21), and small grant (R03). 
Applicants for R01s may request support for up to 5 years.  In FY 1998, the
average total cost per year for new and competing renewal R01s funded by the
Division of Basic Research was approximately $190,000.  Currently, NIAAA Small
Grants are limited to up to 2 years for up to $50,000 per year and NIAAA
Exploratory/Developmental Grants are limited to up to 3 years for up to
$100,000 per year, respectively, for direct costs. Applicants without
extensive preliminary data are urged to submit applications for this PA using
the exploratory/developmental and small grants mechanisms, and to use the
preliminary findings obtained from the R03/R21 mechanisms to submit R01
applications under the regular application receipt dates. 
Exploratory/developmental grants and small grants cannot be renewed. 
Applicants who anticipate submitting a small grant or
exploratory/developmental grant should contact the program staff listed under
INQUIRIES or the NIAAA Home Page at http://www.niaaa.nih.gov for additional
information on these mechanisms.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application, i.e,
as plans for the study are being developed.  Furthermore, the applicant must
obtain agreement from IC staff that the Institute will accept the application
for consideration for award.  Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute or Center who
agreed to accept assignment of the application.  This policy requires an
applicant to obtain agreement for acceptance of both any such application and
any such subsequent amendment. Refer to the NIH Guide for Grants and
Contracts, March 20, 1998 at

Applicants may also submit applications for Investigator-Initiated Interactive
Research Project Grants (IRPG).  Interactive Research Project Grants require
the coordinated submission of related research project grants (R01) from
investigators who wish to collaborate on research, but do not require
extensive shared physical resources.  These applications must share a common
theme and describe the objectives and scientific importance of the interchange
of, for example, ideas, data, and materials among the collaborating
investigators.  A minimum of two independent investigators with related
research objectives may submit concurrent, collaborative, cross-referenced
individual R01 applications.  Applicants may be from one or several
institutions.  Further information on these and other grant mechanisms may be
obtained from the program staff listed in the INQUIRIES section of this PA or
from the NIAAA Web site http://www.niaaa.nih.gov/.

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grants can be
found at https://grants.nih.gov/grants/funding/modular/modular.htm.


It is estimated that up to $2 million will be available to fund approximately
8-10 grants under this PA in FY 2000 and 2001.  This level of support is
dependent on the receipt of a sufficient number of applications of high
scientific merit and availability of funds. The earliest possible award date
is July 1, 2000.  Future applications for regular research grant application
receipt dates will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  Responsibility
for the planning, direction, and execution of the proposed project will be
solely that of the applicant.



HCV infection is a major worldwide cause of acute and chronic hepatitis, liver
cirrhosis and hepatocellular carcinoma (HCC).  In the United States, nearly
four million people are infected with HCV.  Although acute HCV infection may
resolve possibly through induced or innate immunity, the most likely path of
infection results in chronic hepatitis infection.  Liver cirrhosis occurs in a
minority of chronically infected individuals (studies range from approximately
5- 20 percent of individuals).  Chronic HCV infection is now the number one
cause of end stage liver disease requiring orthotopic liver transplantation in
the United States.

Alcoholism afflicts approximately 7-10 percent of Americans at some time in
their lives, and approximately 15 percent of persons with alcoholism will
develop alcoholic cirrhosis.  Chronic alcohol intake is the most frequent
cause of liver disease today and accounts for the majority of the estimated
100,000 alcohol-related deaths each year.  Although ethanol is generally
regarded as directly hepatotoxic, there are considerable differences between
individuals in susceptibility to alcohol-induced liver damage.  For example,
30 percent of diagnosed alcoholics have completely normal liver histology
despite prolonged alcohol abuse, and only 10 to 20 percent of alcoholics
develop liver cirrhosis.  In addition, the dose-response relationship between
total alcohol consumption and development of cirrhosis is not linear.  There
is strong evidence that susceptibility to alcohol-induced liver disease is
under genetic control, perhaps related to differences in the metabolism and
clearance of ethanol. There are also susceptibility and pathogenesis issues
related to gender, with females having apparently lower threshold levels for
the induction of liver pathogenesis.

There are multiple etiologies that result in liver cirrhosis. There is also
evidence to support a potential role for exogenous co-factors in the
development of liver cirrhosis.  The most impressive data support an
association between HCV infection and alcoholic liver disease (ALD).  The
prevalence of HCV is significantly higher among alcoholics than in the general
population: the HCV positive rate in the general population is about 1
percent, 16 percent for alcoholics without liver disease, and nearly 30
percent for alcoholics with liver disease. Studies suggest that HCV
accelerates the development of ALD, and HCV is associated with 22.2 percent of
cases of ALD presenting with acute hepatitis, 84 percent with chronic
hepatitis and 100 percent with HCC.  These studies demonstrate that although
both alcohol and HCV can independently induce liver disease, co-occurrence of
both agents may accelerate the course of liver pathology and/or lead to more
severe injury.  Alcohol intake at any level as well as alcohol abuse may
increase the severity of HCV-induced liver injury possibly by promoting viral
replication, inhibiting clearance of the virus, promoting virulence, or
enhancing host susceptibility to HCV infection of the liver through unknown
changes  in the liver.  Understanding the cellular and molecular events
involved in the initiation and development of liver disease due to the
combined effects of alcohol abuse and HCV infection will allow a better
understanding of disease pathogenesis and thereby promote new paradigms for
prevention and treatment.

Areas of Research Focus

This PA solicits grant applications for research that elucidate mechanism(s)
in the development and progression of liver disease in a setting of combined
alcohol use and HCV infection.  Studies which focus on cellular and molecular
mechanisms of viral pathogenesis, immune responses and liver disease, in the
context of gender, race, and age are encouraged.  Development of animal models
and in vitro experimental systems to study the interactive effects of alcohol
exposure and HCV pathogenesis are highly encouraged. Specifically, studies are
sought that address:

o  History of alcohol use and/or abuse, current use or abuse of alcohol in the
progression of liver disease in individuals with hepatitis C
o  Ethanol and viral replication
o  Alcohol consumption and the development of viral quasispecies or subtypes
o  Ethanol-induced oxidative stress and changes in liver cell metabolism and
HCV progression
o  Ethanol-induced immunosuppression and HCV progression
o  Viral levels, alcohol intake and hepatocellular carcinoma
o  Viral levels, pathogenesis, alcohol intake and outcome measures
o  Cofactors such as iron inducing the progression of ALD and HCV
o  Stellate cell activation in ALD and HCV
o  Treatment of viral hepatitis and/or alcoholism  and progression of liver
o  Co-infection with other viruses such as hepatitis G virus or human
immunodeficiency virus

Although the above research topics represent areas of high interest,
applicants are encouraged to consider other topics within the scope of this

Note to investigators.  In clinical studies, alcohol consumption levels must
be taken into account to differentiate heavy, moderate, and light drinking. 
Other measures to consider are quantity and frequency of drinking (rather than
average number of drinks per time), drinking pattern (i.e., with meals), and
type of beverage consumed.  These characteristics become especially important
in moderate alcohol consumption studies.


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 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, available at the following URL address: 


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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning these policies.


For the first receipt date of December 22, 1999, only, prospective applicants
are asked to submit, by November 24, 1999, a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of the PA in response
to which the application may be submitted.  A letter of intent is not
requested for applications submitted for subsequent receipt dates.

Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NIAAA staff to estimate the potential review workload and to
avoid conflict of interest in the review.  The letter of intent is to be sent

Hepatitis C  PA
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4375
FAX:  (301) 443-6077


The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: 
grantsinfo@nih.gov. The PA title and number must be typed on line 2 of the
face page of the application form and the YES box must be marked.  Page limits
and limits on size of type are strictly enforced.  Non-conforming applications
will be returned without being reviewed.

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewer's and Institute
staff. The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year for R01s, $100,000 per year
for R21s, and $50,000 per year for R03s.  (Applications for R01s that request
more than $250,000 for direct costs in any year must follow the traditional
PHS 398 application instructions.)  The total direct costs must be requested
in accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments and Total Costs [Modular Total Direct plus Facilities and
Administrative (F&A) costs] for the initial budget period Items 8a and 8b
should be completed indicating the Direct and Total Costs for the entire
proposed period of support.

of the PHS 398. It is not required and will not be accepted with the

categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for
each year. This is not a Form page.

o Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm .

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects  ongoing or completed during the last three years; and
- List selected peer-reviewed publications, with full citations.

o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the type
of agreement and the date. All appropriate exclusions must be applied in the
calculation of the F&A  costs for the initial budget period and all future
budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review. The title
and number of the program announcement must be typed in Section 2 on the face
page of the application.

For the first receipt date only, submit a signed, typewritten original of the
application, including the checklist and three signed photocopies in one
package to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, for the first receipt date only, two additional
copies of the application must also be sent to:

Hepatitis C  PA
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20852 (for express/courier service)

Applications for the first receipt date must be received by December 22, 1999. 
Standard application receipt dates will be used thereafter.  All five copies
of an application for a standard receipt date must be sent to the Center for
Scientific Review as described in the PHS-398 application instructions.


Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by the NIAAA.  Incomplete
applications will be returned to the applicant without further consideration. 
Applications that are complete and responsive to the PA will be evaluated for
scientific and technical merit by an appropriate peer review group in
accordance with the review criteria stated below.  As part of the initial
merit review, a process will be used by the initial review group in which
applications receive a written critique and undergo a process in which only
those applications deemed to a have the highest scientific merit, generally
the top half of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the National Advisory
Council on Alcohol Abuse and Alcoholism.

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 the application 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 assigning the overall score,
weighting them as appropriate for each application.  Note that the 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, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

Significance:  Does the study address the goals of the PA?  If the aims of the
study are achieved, how will scientific knowledge be advanced?  Will the study
advance the concepts or methods that drive this field?

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 designs?

Feasibility:  Can the design be implemented (including recruitment of
subjects, cooperation of relevant organizations, and/or collection of
necessary data)?

Innovation:  Does the project employ novel concepts, approaches, theories, or

Investigator:  Are the principal investigator and key research personnel
appropriately trained and well-suited to carry out this work?

Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Does the proposed research take
advantage of the unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional

Budget: Is the requested budget and estimation of time to completion of the
study appropriate for the proposed research?

In addition, plans for the recruitment and retention of subjects will be
evaluated as well as the adequacy of plans to include both genders, minorities
and their subgroups, and children as appropriate for the scientific goals of
the research.

The initial review group will also examine the provisions for the protection
of human and animal subjects and the safety of the research environment.


Applications recommended for approval by the National Advisory Council on
Alcohol Abuse and Alcoholism will be considered for funding on the basis of
the overall scientific and technical merit of the proposal as determined by
peer review, NIAAA programmatic needs and balance, and the availability of


Inquiries concerning this PA 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 Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD  20892-7003
Telephone:  (301) 443-6537
FAX:  (301) 594-0673
Email: tk13v@nih.gov

Raye Z. Litten, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard  MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0796
FAX:  (301) 443-8774
Email:  rlitten@willco.niaa.nih.gov

Direct inquiries regarding fiscal matters to:

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov


This program is described in the Catalog of Federal Domestic Assistance, No.
93.273.  Awards are made under the authorization of the Public Health Service
Act, Sections 301 and 464H, and administered under the NIH policies and
Federal Regulations at Title 42 CFR Part 52 and 45 CFR Parts 74 and 92.  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 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.

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