Full Text AA-95-004


NIH GUIDE, Volume 24, Number 23, June 23, 1995

RFA:  AA-95-004

P.T. 34

  Risk Factors/Analysis 
  Biology, Cellular 
  Biology, Molecular 

National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  October 18, 1995
Application Receipt Date:  November 21, 1995


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking applications for research to determine both the benefits and
risks of moderate alcohol use.  Several cultural and social
definitions for "moderate" alcohol consumption exist, and
epidemiological studies refer to a wide range of drinking as
moderate.  In addition to defining moderate drinking, many important
questions remain unanswered.  The cellular and molecular mechanisms
of the positive association of moderate alcohol use and cardiac
health need to be established.  Further, any negative effects
associated with long term moderate drinking in individuals or
subpopulations need to be delineated.  Answers to such questions will
help identify the tradeoffs involved in an individual's decision
about drinking, and will provide a solid base for formulating public
health policies.  Information obtained about moderate drinking will
also provide a better understanding of the mechanisms involved in
alcohol effects in general.

The purpose of this request for applications (RFA) is to stimulate a
wide range of molecular and cellular studies, as well as
epidemiological, clinical and psychosocial studies on the benefits
and the risks of moderate drinking.  These areas include, but are not
limited to: (1) coronary artery disease; (2) hypertension; (3)
stroke; (4) osteoporosis and breast cancer; (5) interaction with
various medications; (6) trade-offs (risk/benefit analysis); and (7)
psychosocial issues.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Moderate Alcohol Consumption:  Benefits and Risks, is related to the
priority area of consequences of alcohol abuse and alcoholism.
Potential applicants may obtain a copy of Healthy People 2000 (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) Awards.


Research support may be obtained through applications for a regular
research project grant (R01), FIRST (R29) Award,
exploratory/developmental grant (R21), and small grant (R03).
Applicants for R01s may request support for up to five years.  In FY
1995, the average total cost per year for new R01s funded by the
NIAAA was approximately $200,000.  Because the nature and scope of
the research proposed in response to this RFA may vary, it is
anticipated that the size of an award will vary also.

A FIRST (R29) Award application must be for five years.  Total direct
costs for the five-year period may not exceed $350,000 or $100,000 in
any one budget period.  Small grants (R03) and
exploratory/developmental grants (R21) are limited to two years for
up to $50,000/year and $70,000/year, respectively for direct costs.
FIRST (R29) Awards, small grants (R03) and exploratory/developmental
grants (R21) cannot be renewed, but grantees may apply for R01
support to continue research on the same topics.  Potential
applicants for FIRST (R29) Awards, small grants (R03) and
exploratory/developmental grants (R21) should obtain copies of the
specific announcement for these programs from the National
Clearinghouse for Alcohol and Drug Information, P.O. Box 2345,
Rockville, MD 20852, telephone (301) 468-2600 or 1-800-729-6686.
Investigators submitting applications that exceed $500,000 for direct
costs in any one year should contact program staff prior to
submitting an application.

Applicants may submit applications for Investigator-Initiated
Interactive Research Project Grants (IRPG) (refer to PA-94-086, Vol.
23, No. 28, July 29, 1994). Interactive Research Project Grants
require the coordinated submission of related research project grants
(R01) and, to a limited extent, FIRST Award (R29) applications 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
concurrently collaborative, cross-referenced individual R01 and R29
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 under INQUIRIES.


It is estimated that up to $2.0 million in total costs will be
available for approximately 10 grants under this RFA in FY 1996.
This level of support is dependent on the receipt of sufficient
number of applications of high scientific merit.  Although this
program is provided for in the financial plan of NIAAA, the award of
grants pursuant to this RFA is also contingent upon the availability
of funds.  The earliest possible award date is July 1, 1996.


A review of the psychological benefits of moderate drinking suggests
that low levels of alcohol can reduce stress, promote conviviality,
and reduce tension and self- consciousness (Baum-Baicker, 1985).
This RFA focuses on the benefits and risks associated with moderate

1.  Alcohol and Coronary Artery Disease

Numerous epidemiologic studies indicate that moderate drinking is
associated with a protective effect against coronary artery diseases
(e.g., Klatsky et al., 1990; Rimm et al., 1991; Anderson et al.,
1993; Serdula et al., 1995), but not longevity (Criqui and Ringel,
1994).  A recent study showed that light to moderate alcohol
consumption reduced mortality in women, but this benefit appears
largely confined to women at greater risk for coronary heart disease
(Fuchs et al., 1995).  Most of these epidemiological studies consider
the impact of total alcohol consumption over time versus heart
disease.  However, the influence of various drinking patterns (e.g.,
lifelong moderate consumption vs. heavy drinking in youth and
abstinence later, vs. beginning consumption later in life) is not
clear.  In addition, the effects of acute versus chronic alcohol
consumption and coronary artery disease needs clarification.  The
contribution of other life style factors (e.g., aspirin consumption,
exercise, dietary habits, marital status, smoking, stressful events,
and social class) to the observed effect on coronary arteries needs
to be elucidated.  A recent study has attributed some of the apparent
protective effects of moderate drinking to physical activity and
other health practices (Barrett et al., 1995).

Understanding the cellular and molecular mechanisms by which alcohol
reduces the risk of coronary artery disease is important.  Research
performed hitherto on the mechanisms of the protective effect is
suggestive, but not conclusive.  While some studies have shown that
chronic alcohol consumption increases HDL cholesterol (Hartung et
al., 1990; Langer et al., 1992), others have reported that the
subspecies HDL3, which is associated with moderate drinking in
several studies, has low protective effect (Miller et al., 1981).
Yet other studies have shown that both HDL2 and HDL3 are associated
with light drinking (Haffner et al., 1985).  These studies suggest an
effect of alcohol on HDL; however, the mechanism of action has not
been firmly established.  Some studies hypothesized that this effect
is due to an alcohol-induced defect in cholesteryl ester transfer
protein (CETP) (Savolainen et al., 1990; Hirano et al., 1992;
Hannuksela et al., 1992).  Further studies are needed to clarify the
effects of alcohol on HDL, CETP and on lipoproteins.

Results from a number of studies have demonstrated that acute alcohol
consumption reduces platelet aggregation and coagulation (e.g.,
Renaud and deLorgeril, 1992), which may partly explain the decrease
in risk of coronary artery disease associated with moderate drinking.
Healthy volunteers who consumed alcohol in sufficient amounts to
produce blood alcohol levels less than 100 mg/dL showed an increase
in the blood concentration of prostacyclin, which counters the
platelet-aggregating effects of thromboxane A2 (Landolfi and Steiner,
1984).  The extent to which this effect contributes to the reduction
in cardiac risk is unknown.  Furthermore, the interaction between
alcohol and anticoagulants (aspirin, coumarin derivatives, etc.), and
the relative roles of endothelin, nitric oxide, thromboxane A2,
prostacyclin and adenosine in the protective effect have not been
extensively studied.

Also, antioxidants, such as flavonoids (Demrow et al., 1995) or
resveratrol (Siemann and Creasy, 1992) are claimed to contribute to
the cardio-protective effect of wine, but this issue remains
controversial. The role of antioxidants, if any, needs clarification.
Epidemiologic studies have shown that all alcoholic beverages, i.e.
beer, wine, and distilled spirits (even those that do not contain an
appreciable amount of antioxidants) confer protective effects
(Seigneur et al., 1990; Klatsky et al., 1992), although a recent
study in Copenhagen found decreased risk only with wine (Gronbek,

Other questions that need to be addressed include:  Are there gender
differences in the extent of alcohol-induced coronary artery
protection?  If so, what is the relative contribution of
alcohol-induced increases in estrogens, especially in post-menopausal
women, to the overall effect?  What is the role of phytoestrogens
that are present in certain drinks (e.g., Bourbon) in producing the
observed effect?

2.  Alcohol and Hypertension

Epidemiological studies from numerous countries have demonstrated
that chronic heavy alcohol consumption is associated with
hypertension (see review by McMahon, 1987).  Although hypertension
has not been directly associated with moderate drinking, some studies
have shown a positive linear relationship between blood pressure and
amount of alcohol consumed, especially in men (Paulin, 1985; Klatsky
et al., 1986; Rimm et al., 1991).  Does moderate consumption lead to
hypertension over time?  If so, what is the threshold level of
consumption that does not produce hypertension?  Women who consume
moderate amounts of alcohol did not show tendency for developing
hypertension.  Why?

Whether or not chronic moderate drinking results in hypertension is
not clear. However, studies to determine the mechanisms by which
heavy alcohol consumption induces hypertension are needed to design
effective treatment protocols.

3.  Alcohol and Stroke

Stroke, both ischemic and hemorrhagic, is the third leading cause of
death in the United States.  Once stroke occurs, the prognosis is
poor.  Epidemiologic studies suggest that moderate alcohol
consumption reduces the risk of ischemic stroke, especially in
Caucasian populations of both genders (Gill et al., 1986, 1988;
Stampfer et al., 1988).  This effect was not observed in a Japanese
population (Tanaka et al., 1982, 1985; Kono et al., 1986).  In
contrast, moderate alcohol consumption was associated with increases
in the risk of hemorrhagic stroke in all populations (Donahue et al.,
1986; Stampfer et al., 1988).  The cellular and molecular mechanisms
by which moderate drinking reduces the risk of ischemic stroke in
certain populations, and increases the risk of hemorrhagic stroke are
not clear.  Are dietary factors involved?  Why does alcohol increase
risk from hemorrhagic stroke?  Does interference with platelet
function (Rand et al., 1988; Benistat and Rubin, 1990) play a role?
Is alcohol-induced increase in prostacyclin levels (Mikhailidis et
al., 1990) involved in this effect?

Oral contraceptives use is associated with an appreciable increase in
risk of subarachnoid hemorrhage (Petiti et al., 1979).  Whether or
not moderate alcohol consumption interacts with oral contraceptives
to increase the risk of hemorrhagic stroke needs to be clarified?
Alcohol intake by women at increased risk has not been examined.

4.  Alcohol, Osteoporosis, and Breast Cancer

Moderate alcohol consumption is positively correlated with bone
mineral density in males and females, especially in post-menopausal
women (Laitinen et al., 1991; Holbrook and Barrett-Conner, 1993).
This finding suggests that moderate alcohol consumption may help in
reducing osteoporosis and, consequently, decrease the risk of
fractures.  However, other studies indicated the opposite effect
(Hernandez-Avila et al., 1991).  Carefully designed cellular and
molecular studies may elucidate the effects of alcohol on bone

The association between moderate alcohol consumption and breast
cancer is controversial.  While some epidemiological studies have
concluded that even modest alcohol consumption is associated with
increased risk of breast cancer (Colditz, 1992) in women (Longnecker,
1994, estimated that four percent of the 150,000 cases/year is
attributable to alcohol), others did not show such a relationship
(Ewertz, 1991).  The contribution of alcohol consumption to breast
cancer risk needs to be delineated.  If indeed moderate drinking
increases the risk of breast cancer, what are the cellular and
molecular mechanisms of such an effect?  Does alcohol-induced
increase in estrogen play a role?  Do alcohol-induced microsomal
enzymes affect the biotransformation of procarcinogens to

5.  Interaction Between Moderate Alcohol Consumption and Various

Many medications (anesthetics, antibiotics, anticoagulants,
antidepressants, oral hypoglycemics, antihistamines, antipsychotics,
antiseizure, cardiovascular, narcotics, analgesics, sedatives, etc.)
can interact with alcohol leading to serious consequences.  Whether
moderate drinking results in blood alcohol levels that may adversely
interact with medications, especially in the elderly, is an issue of

6.  Trade-Offs (Risk/Benefit Analysis)

In addition to defining what moderate drinking is, studies aimed at
investigating possible trade-offs between the benefits and risks of
moderate drinking (in terms of morbidity and mortality) for the
population as a whole and for specific subgroups are encouraged.
What are the benefits versus risks for different groups of people
(e.g., elderly, young adults, smokers).

7.  Psychosocial Issues

Even modest amounts of alcohol may increase morbidity from existing
physical disorders, cause relapse among abstaining alcoholics, affect
performance or judgment in critical situations, increase accidents
and falls among low tolerance populations (e.g., the elderly), and
exacerbate existing family and work problems.  For groups who do
drink moderately, more detailed information is required to formulate
appropriate advice.  In particular, health care professionals are
increasingly encouraged to advise patients about "safe drinking"
limits.  This may include selective advice to at-risk groups such as
anticipatory guidance to adolescents and the elderly.  Research is
needed to:  (a) understand how vulnerable populations, the population
at large, and health-care professionals interpret moderate drinking
messages of various types (e.g., promoting cardiovascular risk
reduction, reduction of behavioral consequences of heavy drinking);
(b) examine how patients respond to different types of advice from
their health-care providers concerning the benefits and risks of
moderate drinking; (c) increase knowledge on the psychosocial and
environmental contexts in which moderate drinking occurs, how context
mediates the consequences of moderate drinking, and what changes
might be implemented to make moderate drinking patterns less


It is the policy of NIH that women and members of minority groups and
their subpopulations must be included in all NIH-supported biomedical
and behavioral research projects involving human subjects, unless a
clear and compelling rationale and justification is provided that
inclusion is inappropriate with respect to the health of the subjects
or the purpose of the research.  This new policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some provisions that are substantially
different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH
Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994.

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


Prospective applicants are asked to submit, by October 18, 1995, 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 RFA in response to
which the application may be submitted.  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 avoid
conflict of interest in the review.

The letter of intent is to be sent to:

RFA:  AA-95-004
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
FAX:  (301) 443-6077


The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 6701 Rockledge Drive, Room 3032, msc 7762, Bethesda, MD
20892, telephone 301-710-0267; and from the NIAAA program
administrators listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
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 2a 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.  Applications for the FIRST award (R29) must include at
least three sealed letters of reference attached to the face page of
the original application.  FIRST award (R29) applications submitted
without the required number reference letters will be considered
incomplete and will be returned without review.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies in one package to:

BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application
must also be sent to:

Mark Green, Ph.D.
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003  (20852 for express mail)

Applications must be received by November 21, 1995.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) 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 DRG 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 be prepared as a revised application and include an introduction
addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness by the NIAAA.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, DRG staff will 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 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
the NIAAA in accordance with the review criteria stated below.  As
part of the initial merit review, a triage process may be used by the
initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration, and the
Principal Investigator and the official signing for the applicant
organization will be notified.  The second level of review will be
provided by the National Advisory Alcoholism and Alcohol Abuse

Review Criteria

Criteria to be used in the scientific and technical merit review of
alcohol research grant applications are the following:

1.  The scientific, technical, or medical significance and
originality of the proposed research.

2.  The appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research.

3.  The adequacy of the qualifications (including level of education
and training) and relevant research experience of the principal
investigator and key research personnel.

4.  The availability of adequate facilities, general environment for
the conduct of the proposed research, other resources, and
collaborative arrangements necessary for the research.

5.  The reasonableness of budget estimates and duration in relation
to the proposed research.

6.  Adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will
also be evaluated.

7.  Where applicable, the adequacy of procedures to protect or
minimize effects on human and animal subjects and the environment.

The review criteria for FIRST Awards (R29), Small Grants (R03) and
Exploratory/Developmental Grants (R21) are contained in their program


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 application as determined by peer review, NIAAA programmatic
needs and balance, and the availability of funds.


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

Direct inquiries regarding biomedical aspects of proposed research

Sam Zakhari, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 402
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0799
FAX:  (301) 594-0673
Email:  SZakhari@Willco.NIAAA.NIH.Gov

Direct inquiries regarding epidemiological aspects of proposed
research to:

Mary C. Dufour, M.D., M.P.H.
Deputy Director
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 400
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-3851
FAX:  (301) 443-7043
Email:  MDufour@Willco.NIAAA.NIH.Gov

Direct inquiries regarding psychosocial aspects of proposed research

Kendall Bryant, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 505
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-8820
FAX:  (301) 443-8774
Email:  KBryant@Willco.NIAAA.NIH.Gov

Direct inquiries regarding fiscal matters to:

Joseph Weeda
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  JWeeda@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 PHS policies and Federal Regulations at Title
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing 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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