S-ADENOSYL-L-METHIONINE (SAME) AND LIVER DISEASE

RELEASE DATE:  January 30, 2002

RFA:  RFA-AA-02-011

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
 (http://www.niaaa.nih.gov/)
The Office of Dietary Supplements (ODS)
 (http://www.nih.gov/icd/od)
The National Center for Complementary and Alternative Medicine (NCCAM)
 (http://www.nccam.nih.gov)

LETTER OF INTENT RECEIPT DATE:  April 15, 2002
APPLICATION RECEIPT DATE:       May 15, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to become Principal Investigators
o Where to send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE

The purpose of this RFA is to invite applications for grants proposing 
innovative basic and preclinical research to understand how SAMe may be 
effective in the treatment of liver disease caused by alcohol and other factors 
such as hepatitis C virus (HCV). Liver disease progresses from steatohepatitis 
to fibrosis, and cirrhosis, which is a major cause of illness and death in the 
USA. Oxidant stress plays a key role in pathogenesis of liver disease. SAMe, a 
dietary supplement, is a methyl donor for biochemical methylation reactions and 
a precursor of glutathione, the main hepatocellular antioxidant. SAMe has been 
shown to attenuate liver injury caused by alcohol and other hepatotoxins in 
animal models, and these changes were associated with restoration of depleted 
hepatic glutathione levels. Understanding the mechanisms by which SAMe 
attenuates liver injury caused by alcohol and/or HCV, or other hepatotoxins may 
provide useful information for full-scale human clinical trials.   

RESEARCH OBJECTIVES

Liver disease characterized by fatty liver, hepatitis, fibrosis, and cirrhosis 
is a major cause of illness and death worldwide. It is the fourth leading cause 
of death among adult men of 24-65 years residing in urban areas of the USA. 
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.  
Approximately 50% of all deaths due to liver cirrhosis involve alcohol abuse and 
alcoholism. Alcoholic liver disease is exacerbated by HCV infection, which is a
worldwide health problem, affecting approximately 170 million persons. 

Those who abuse alcohol are more easily infected with HCV and are more likely to 
experience persistent, long-term infection. Excessive alcohol consumption 
increases viral burden and interferes with antiviral therapy. Their liver 
disease is more likely to progress to cirrhosis and hepatocellular carcinoma. 
Currently HCV is treated with interferon plus ribavirin, a combination, which 
has multiple drawbacks that limit its usefulness. Current therapies are 
effective in clearing the HCV virus in only 30-40% of the cases. Recent research 
indicates that oxidant stress is in part responsible for the liver damage seen 
in HCV infection. SAMe may be a useful adjunct in the treatment of HCV.  

Various factors have been implicated in the initiation of liver injury, such as 
endotoxin, tumor necrosis factor-alpha (TNF-alpha), and free radicals. Free 
radicals can activate nuclear transcription factor-kB (NF-kB), which increases 
the transcription of TNF-alpha, a proinflammatory cytokine that can initiate 
hepatitis. Several sources of free radicals, including NADPH oxidase, xanthine 
oxidase, CYP2E1, and lipooxygenase, have been identified in Kupffer cells of the 
liver. Using animal models and cultured liver cells, researchers have 
established a firm link between generation of free radicals and development of 
alcohol-induced liver injury. Thus, complementary and alternative approaches 
that diminish oxidant injury may have merit in terms of protecting the liver 
from free radical induced damage.

Researchers have investigated the roles of dietary supplements, having 
antioxidant properties, in the treatment of liver disease caused by different 
agents including alcohol. Antioxidants that are being studied include N-
acetylcycteine, vitamin E, polyenylphosphatidylcholine, and silymarin. The 
potential usefulness of the SAMe in liver disease is based on the 
following information. 

1) SAMe is a precursor of glutathione, which is an endogenous antioxidant.
2) Chronic ethanol intake depletes hepatic SAMe levels that are associated with 
impaired metabolism of methionine, a precursor of SAMe. 
3) SAMe has been shown to attenuate hepatotoxicity caused by TNF-alpha, which is 
known to trigger alcoholic hepatitis. 
4) In animal models, SAMe administration restored mitochondrial glutathione 
depletion and attenuated liver injury caused by alcohol and other hepatotoxins. 

Possible topics responsive to this RFA include, but are not limited to:

o Investigation of the mechanisms by which hepatotoxic agents, including 
alcohol, impair methionine (SAMe precursor) metabolism and its impact on hepatic 
SAMe and glutathione levels?

o Identification of the role of folate deficiency in methionine metabolism, and 
ultimately SAMe and glutathione levels.

o Investigation of the mechanisms by which hepatototxins deplete hepatic 
mitochondrial glutathione levels and impair mitochndrial functions, and the role 
of SAMe in restoring these defects.

O Determination of whether providing supplemental SAMe affects circulating and 
cellular levels of glutathione. Study the pharmacokinetics of SAMe in 
animal models.  

o Investigation of the mechanisms by which impaired SAMe synthesis predisposes 
to liver injury. Is it due to hypomethylation and/or oxidant stress caused by 
depressed glutathione levels, or by other mechanisms? 

o Determination of whether SAMe levels influence the activation of NF-kB and/or 
gene expression of TNF-alpha and other inflammatory cytokines.

o Elucidation of the stages of liver disease that are more responsive to 
SAMe treatment

o Exploration of whether SAMe affects immune functions, and whether this immune 
modulation by SAMe has a salutary effect on liver function. 

o Investigation of the potential of SAMe for use as adjunctive therapy for 
hepatitis C and whether this approach would make the present therapy more 
effective and better tolerated.

o Investigation of whether SAMe diminishes virally-induced liver damage and 
modifies the progression of HCV-related liver disease.

MECHANISMS OF SUPPORT

This RFA will use NIH research project grant (R01), exploratory/developmental 
grant (R21), and small grant (R03) award mechanisms. As an applicant you will be 
solely responsible for planning, directing, and executing the proposed project. 
This RFA is a one-time solicitation. Future unsolicited, competing-continuation 
applications based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer review 
procedures. The anticipated award date is September 28, 2002.

This RFA 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.

FUNDS AVAILABLE 
 
The participating ICs intend to commit approximately $1.5 million in FY 2002 to 
fund 6 to 10 new and/or competitive continuation grants in response to this RFA. 

Applicants for R01s may request a project period of up to 5 years and a budget 
for direct costs of up to $250,000 per year. Currently, small grants (R03) are 
limited to 2 years for up to $50,000 per year for direct costs, and 
exploratory/developmental grants (R21) are limited to $100,000 per year for 
direct costs for up to 3 years. Exploratory/developmental grants and small 
grants cannot be renewed, but grantees may apply for R01 support to continue 
research on the same topics.

Because the nature and scope of the proposed research will vary from application 
to application, it is anticipated that the size and duration of each award will 
also vary. Although the financial plans of the ICs provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. At 
this time, it is not known if this RFA will be reissued. 

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 inquiries concerning this RFA and welcome the opportunity to answer 
questions from potential applicants.  Inquiries may fall into three areas:  
scientific/research, peer review, and financial or grants management issues:

O Direct your questions about scientific/research issues related to alcohol 
abuse and alcoholism 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

O Direct your questions about scientific/research issues related to 
complementary and alternative medicine to:

Marguerite Evans
Program Officer
National Center for Complementary and Alternative Medicine
6707 Democracy Blvd.
Democracy 2, Suite 401
Bethesda, MD  20892-5475
Telephone:  301-402-5860
FAX:  301-480-3621
Email:  me16o@nih.gov or evansm@mail.nih.gov

O Direct your questions about scientific/research issues related to dietary 
supplements to:

Rebecca B. Costello, Ph.D.
Office of Dietary Supplements
Office of Disease Prevention, Office of the Director
Building 31, 1B29
Bethesda, MD  20892
Phone:  301-435-2920
Fax:  301-480-1845
Email:  CostellB@od.nih.gov

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

Judy Fox Simons
Acting 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) 443-2434
Email:  jsimons@willco.niaaa.nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 IC staff to estimate the potential review workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document. The letter of intent should be sent to:

Extramural Project Review Branch 
ATTN: AA-02-011
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Room 409, MSC 7003 
Bethesda, MD  20892-7003 (for express mail, use Rockville, MD  20852) 

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) 710-0267, 
Email:  GrantsInfo@nih.gov.
 
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.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label. Failure to use this label could 
result in delayed processing of the application such that it may not reach the 
review committee in time for review.  In addition, the RFA title and number must 
be typed on line 2 of the face page of the application form and the YES box must 
be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the 
application, including the Checklist, and three 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)
 
At the time of submission, two additional copies of the application and five 
copies of any appendix material must be sent to:

Extramural Project Review Branch 
ATTN:  AA-02-011
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Room 409, MSC 7003 
Bethesda, MD  20892-7003 (for express mail, use Rockville, MD  20852) 

APPLICATION PROCESSING: Applications must be received by the application receipt 
date listed in the heading of this RFA. If an application is received after that 
date, it will be returned to the applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA 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 substantial revisions of 
applications already reviewed, but such applications must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the appropriate IC.  

Incomplete applications will be returned to the applicant without further 
consideration. And, if the application is not responsive to the RFA, CSR staff 
may contact the applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited applications 
at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
NIAAA in accordance with the review criteria stated below. As part of the 
initial merit review, all applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will 
be discussed and assigned a priority score
o Receive a second level review by the NIAAA or NCCAM National Advisory Council.  

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:

o 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.

o 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)

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

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    April 15, 2002
Application Receipt Date:         May 15, 2002
Peer Review Date:                 July - August, 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 28, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic 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_2001.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.

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 RFA 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 RFA 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.

The Office of Dietary Supplements (ODS) was mandated by Congress in 1994 and 
established within the Office of the Director, National Institutes of Health 
(NIH). The Dietary Supplement Health and Education Act (DSHEA) [Public Law 
103-417, Section 3.a] amended the Federal Food, Drug, and Cosmetic Act "to 
establish standards with respect to dietary supplements." This law authorized 
the establishment of the ODS.

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