This Program Announcement expired on January 10, 2005.

MECHANISMS OF ALCOHOL-INDUCED TISSUE INJURY

Release Date:  December 13, 2001

PA NUMBER:  PA-02-035 (This PA has been reissued, see PA-05-074)
 
National Institute on Alcohol Abuse and Alcoholism
 (http://www.niaaa.nih.gov/)

THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER 
YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 
(REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The Division of Basic Research of the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) invites grant applications to study the underlying cellular 
and molecular mechanisms by which chronic ethanol ingestion initiates tissue 
injury. Virtually every tissue is impacted negatively by alcohol abuse, and 
the resulting pathological conditions contribute to increased mortality and 
morbidity among all groups and genders. The NIAAA is especially interested in 
pursuing research that elucidates mechanisms of injury common to many body and 
organ systems, with the goal of developing therapeutic strategies to serve 
multiple alcohol-related disorders. Projects that bring together investigators 
in diverse scientific disciplines including microbiology, immunology 
(including innate defenses and mucosal immunology), biochemistry, pathology, 
molecular genetics, bioengineering, imaging technology, and mathematical 
modeling are encouraged.  

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 Program Announcement (PA), 
"Mechanisms Of Alcohol-Induced Tissue Injury," 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/.

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. Applications are also accepted from scientists at foreign 
institutions conducting unique research on alcohol and organ damage.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project 
grant (R01), Small Grant (R03), and Developmental/Exploratory Research Grant 
(R21) award mechanisms.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this PA may 
not exceed five years.

The R03 and R21 awards are to demonstrate feasiblity and to obtain preliminary 
data for future R01 projects.  They are intended to provide initial support 
for new investigators, allow exploration of new directions for established 
investigators, and stimulate investigators from other areas to lend their 
expertise to research within the scope of this announcement.  Applicants for 
the R03 must limit their requests to $50,000 direct costs per year for up to 
two years.  Applicants for the R21 must limit their requests to $100,000 per 
year for up to three years.  These grants are not renewable, continuation of 
projects developed under these programs will be through the R01 mechanism. 

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

RESEARCH OBJECTIVES

Excessive alcohol intake often results in life-threatening medical disorders 
stemming from selective cell and tissue injury.  Moreover, ethnic, gender and 
age differences in onset and severity of clinical pathology are observed.  
Although the underlying physiology and biochemistry of all cells is similar, 
manifestations of alcohol damage in adult and fetal tissue and organ systems 
may be quite different, depending on the specificity and course of the disease 
following the alcohol insult.  The initiating events at the molecular and 
cellular levels leading to alcoholic hepatitis, pancreatitis, immune system 
dysfunction, lung injury, cardiovascular problems, neoplasia, bone disorders, 
brain tissue injury and peripheral neuropathy are not fully understood. 
However, evidence suggests that some common underlying mechanisms of tissue 
injury induction may be at work. For example, inflammatory mediators are 
involved in hepatitis, pancreatitis, and vascular disorders associated 
with alcohol abuse.  Oxidant stress caused by alcohol metabolism is a 
common element in cellular injury in liver, pancreas, lung, and brain. Topics 
of interest may include enhancement of tissue injury by inflammatory mediators 
and their modifications, generation of reactive oxygen species during ethanol 
metabolism, induction of pro-apoptotic, anti-apoptotic or other pathways.  
Other areas of interest include the horizontal transfer of active genetic 
elements through apoptotic bodies, and the differential expression of genes 
that participate in cell injury and regulate downstream signaling pathways. 
Approaches such as DNA microarrays and protein chip technology that can 
identify changes in gene expression and protein modifications that trigger 
injury in multiple tissues are encouraged.  The knowledge gained from this 
program initiative will provide the foundation for development of new 
therapeutics to control or modify negative outcomes of chronic alcohol abuse. 
Areas of investigation under this PA could include, but are not limited to:

o  Determination of how shifts in redox states and generation of free radicals 
during ethanol metabolism may contribute to cellular damage.

o  Determination of the contribution of oxidative stress in cellular systems 
to organ injury and the potential value of antioxidant therapy.

o  Elucidation of alcohol"s effects on cell adhesion/homing 
molecules/endothelial cell signal processing in the initiation of organ 
injury.

o  Elucidation of the interactions between gene regulatory elements and 
factors that control developmental, tissue-specific, and temporal expression 
of alcohol metabolizing enzymes.

o  Identification of genes and proteins that are expressed or repressed 
coincident with cell damage, induction of cytokines/chemokines, and/or 
induction of cell death pathways due to alcohol metabolism. 

o  Determination of the genetic predisposition for cell/tissue damage due to 
alcohol metabolism.

o  Determination of the mechanistic basis for adult, fetal, racial/ethnic and 
gender-based differences in clinical manifestations of organ injury.

O  Determination of the initiation, progression, and maintenance of tissue 
injury using targeted mutations.

o  Determination of how, in the presence of alcohol, the cellular response to 
external stimuli initiates a pro-apoptotic or anti-apoptotic signal and the 
downstream consequence of this in susceptible organs. 

o  Elucidation of the roles of ethanol and ethanol metabolites, coincident 
with other factors such as viruses (including HIV and hepatitis C),iron 
overload, antioxidant depletion, and regulatory peptides on inflammatory and 
immune responses and their molecular signaling pathways.

o  Elucidation of the role of vascular-organ interface disruption in ethanol 
induced organ injury

o  Determination of the relative roles of ethanol and ethanol induced toxic 
substances (ammonia, accumulation of endogenous benzodiazepines associated 
with GABA-A, neurotransmitter dysfunction, abnormal levels of 
tryptophan/serotonin, and endogenous opioids) in initiating mechanisms of 
brain damage (as seen in hepatic encephalopathy).

o  Identification of the cellular signals that stimulate stem cells to replace 
damaged tissue and examine the effects of ethanol on stem cell function.

o Determination of the ability of ethanol and its metabolites to disrupt the 
function of the blood brain barrier as a factor in central nervous system 
damage.

o Examination of the cellular and molecular mechanisms of alcohol-induced 
peripheral neuropathy.

o Determination the role of excito-toxicity during withdrawal.

o Determine the role of signaling cascades (CREB, G-proteins, kinases, 
phosphatases) in the development of ethanol-induced tissue injury.

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 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

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://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 the policy.

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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
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 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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants and will be accepted at the standard application 
deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the 
application kit.  This version of the PHS 398 is available in an interactive, 
searchable format.  For further assistance contact GrantsInfo, Telephone 
301/435-0714, Email:  GrantsInfo@nih.gov.

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 application must 
obtain agreement from the IC staff that the IC 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 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.

Applicants planning to use the NIAAA R03 or R21 grant mechanism should consult 
the respective PAs for these mechanisms for additional guidance on preparing 
applications. The URL for the R03 is 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, the URL for the R21 
is http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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, reviewers and NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.

The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened in accordance with the 
standard 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 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.

(1) 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?

(2) 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?

(3) 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?

(4) 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)?

(5) 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The 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.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o  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.

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.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Denise A. Russo, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism 
Willco Building, Room 402 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 402-9403
FAX:  (301) 594-0673
Email:  DRusso@mail.nih.gov

Direct inquiries regarding fiscal matters to:

Judy Simons 
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Room 504 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4704
FAX:  (301) 443-3891
Email:  js182a@nih.gov

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance No. 
93.273.  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 and Federal Regulations 42 CFR 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 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, and 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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