PEPTIDE REGULATION OF ALCOHOL INTAKE

Release Date:  August 23, 1999

PA NUMBER:  PAS-99-156

National Institute on Alcohol Abuse and Alcoholism

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

THIS PROGRAM ANNOUNCEMENT (PA) USES THE "MODULAR GRANT" AND "JUST-IN-TIME"
CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION
INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS
PA.

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites
applications to identify peptides and their receptors that regulate alcohol
consumption, ultimately leading to an understanding of their mechanism(s) of
action. Although not exclusive, several areas have potential for further
investigation including the hypothalamic-pituitary-adrenal axis, opioid
peptides, the renin-angiotensin system, plus the group of peptides regulating
food intake and energy balance, exemplified by leptin and neuropeptide Y. 
Evidence indicates that hormones regulating food intake (such as leptin and
neuropeptide Y) may act upon the same neural circuitry in the brain that
controls alcohol consumption.  Therefore, studying the role of these peptides
in the regulation of alcohol consumption is warranted.  The goal of this
initiative is to elucidate the role of peptides in pathological alcohol
consumption, suggesting novel pharmacotherapeutic approaches for alcoholism.

HEALTHY PEOPLE 2000

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, Peptide Regulation of Alcohol Intake, 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.

ELIGIBILITY

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.

MECHANISM OF SUPPORT

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 for direct
costs and NIAAA Exploratory/Developmental Grants are limited to up to 3 years
for up to $100,000 per year 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 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 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 http://grants.nih.gov/grants/funding/modular/modular.htm.

FUNDS AVAILABLE

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.

RESEARCH OBJECTIVES

Background

Alcohol abuse and alcoholism afflict nearly 14 million Americans, resulting in
more than 105,000 deaths annually, and the financial toll is approaching $167
billion in the United States this year.  Nationwide, 20รพ40 percent of
hospitalizations involve people being treated for complications related to
drinking.  Thus, understanding the reasons why some people drink to excess is
an important goal of the NIAAA.  Actions of alcohol on the brain, including
the neuroendocrine system, are essential to understanding the mechanisms of
alcohol abuse and alcoholism.

Alcohol is a simple molecule with numerous actions on the body, particularly
the brain.  In addition to the classical neurotransmitters, many neuropeptides
have been identified and are believed to act as modulators of
neurotransmission.  Although many actions of alcohol on neurotransmitters have
been reported, the potential role of various peptides is not well understood. 
The most prominent peptides in alcohol research are the opioids because of the
therapeutic use of naltrexone, an opioid antagonist, for treating alcoholism. 
Other peptides have not been extensively studied, including those with
peripheral actions that might modify alcohol intake, such as the gut peptide
cholecystokinin.  Thus, examining the role of various peptides in the actions
of alcohol presents an opportunity to explore new areas that may yield new
approaches for treating alcoholism.

RESEARCH AREAS OF INTEREST

Based upon the information provided below, one has a diverse array of peptides
and receptors, including some recently discovered molecules (e.g., the
orexins) from which to study their individual and collective contributions to
the regulation of alcohol consumption in humans and animals. Investigators are
encouraged to explore their own lead candidates, or alternatively, pursue the
discovery of new molecular entities.  In either situation, research is
encouraged to identify the following when relevant to the actions and/or
consequences of alcohol use: the anatomical locations of  peptides within the
brain and in the periphery (if relevant); crucial neural pathways that mediate
peptidergic effects; which peptides and/or other molecules are directly up- or
down-regulated in the process; the role of peptide transport from the
circulation to the CNS, and its potential perturbation by alcohol; and, at the
cellular level, the characterization of peptide-receptor interaction(s)
triggering specific signal transduction pathways. Examples of research areas
of interest are described below.

1. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ALCOHOL INTAKE

The association between stress and the onset of alcohol consumption is a well-
recognized phenomenon, from which the term, "tension-reduction hypothesis of
alcohol use" originated.  Stress or single doses of alcohol stimulate the HPA
axis, eliciting the release of corticotropin releasing factor (CRF) from the
hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and
glucocorticoids from the adrenals.  Paradoxically, chronic alcohol intake
depresses all peptides associated with the HPA axis, including reduced
cerebrospinal fluid levels of CRF, blunted ACTH responses to either naloxone
or CRF, and decreased responsiveness of the adrenals to CRF or ACTH.  The
anatomical site(s) on which alcohol alters CRF levels remains to be
determined, and may be strain- and/or species-specific.  For instance,
alcohol-preferring (P) rats have significantly lower CRF levels in the
hypothalamus, amygdala and prefrontal cortex than non-preferring (NP) rats. 
Also, high alcohol intake in Wistar rats correlates with elevated hypothalamic
CRF levels and depressed pituitary and pons CRF levels.

Animal studies suggest a relationship between ACTH levels and alcohol
consumption, with gender being a contributing factor (see review by Maickel
and Sprague, 1995).  Rats repeatedly injected with ACTH (but not stressed)
exhibited comparable increases in alcohol consumption to post-stressed rats. 
Female Sprague-Dawley rats possess higher basal ACTH plasma levels and lower
post-stress ACTH levels than males from this strain, and these values are
predictive of relative alcohol intake patterns.

In humans, plasma ACTH levels in non-alcoholic sons from alcoholic and non-
alcoholic families differ.  Family history positive (FHP) sons exhibit lower
basal plasma ACTH levels and lower ACTH peak responses to CRF than their
family history negative (FHN) counterparts.  However, following dual
administration of alcohol and CRF, peak ACTH levels in FHN subjects are
reduced substantially but remain unchanged in FHP subjects.  These findings
are consistent with the general reduction in other responses to alcohol.

More research is needed about the role of CRF and ACTH in regulating alcohol
intake. Because of varied responses to alcohol by males and females, studies
of gender differences are especially encouraged. In addition to the general
areas of investigation described above, research is encouraged (but not
limited) to:

o  Characterize the mechanisms by which alcohol interferes with CRF release.

o  Determine whether a reduced HPA response to alcohol in FHP sons could be a
marker of susceptibility to alcoholism.

2.  THE OPIOID SYSTEM AND ALCOHOL INTAKE

Naltrexone, a non-selective opioid antagonist, is an FDA approved drug for
treating alcoholism.  However, the mechanisms by which it works are not
clearly understood.  Studies in animals and humans suggest that endogenous
opioids may regulate alcohol consumption.  Naltrexone and naloxone suppress
alcohol consumption and attenuate intoxication observed in animals and humans
(see review by Froehlich, 1993).  Moreover, additional animal studies
demonstrate that antagonists selective for mu or delta opioid receptors are
likewise effective in reducing alcohol consumption.  Finally, opioid receptors
may regulate dopamine release in mesolimbic pathways and alcohol-seeking
behavior.  Both alcohol and opioids release dopamine from the nucleus
accumbens through actions on opioid receptors.  Naltrexone and its analogues
antagonize alcohol-induced increases in dopamine release and reduce alcohol
intake.

Opioids may act as primers for further alcohol consumption.  If ethanol
exposure releases endogenous opioid peptides, a subject may be primed to
continue drinking.  When naltrexone is administered, this priming effect is
inhibited.  Thus, little incentive exists to consume more ethanol.  Indeed,
recent clinical studies support the rodent studies.  Both alcoholics and
nonalcoholics given naltrexone report being less high when they consume
ethanol.  These data suggest that abstinent alcoholics have fewer relapses
because they are not obtaining the positive reinforcement they expect by
ingesting ethanol.  This effect can persist during the first six months after
therapy is discontinued.

Acute alcohol consumption increases endorphin and enkephalin gene expression,
enhancing opioid release from brain and pituitary sites in rodents and humans. 
Despite contrary evidence that chronic alcohol consumption decreases opioid
gene expression in regions of the rat brain and depresses beta-endorphin
release in the brains of alcoholics, chronic alcohol intake nonetheless
elevates opioid levels.  The explanation for this sustained opioid elevation
is a compensatory reduction in opioid enzymatic degradation.  Thus, although
acute and chronic alcohol exposures activate the endogenous opioid system by
different means, they both reinforce sustained alcohol consumption.

Congenital anomalies of the opioid system may predispose some individuals to
over-consume alcohol.  After human subjects ingest alcohol, their opioid
systems become more responsive.  However, after chronic ingestion of alcohol,
their opioid systems become less responsive.  Defective opioid systems have
also been described in alcohol-naive ethanol-preferring inbred rodent lines
and in children of alcoholics before they initiate alcohol-drinking behavior. 
At the molecular level, differences in opioid peptide content, opioid receptor
density and opioid secretion were detected when alcohol-preferring mice were
compared with alcohol-avoiding mice.

Further research is needed to gain a better understanding of the role of
opioid peptides in alcohol consumption. Studies are encouraged to include both
genders. In addition to the general areas of investigation described above,
research is encouraged (but not limited) to:

o  The mechanism(s) by which current opioid antagonists reduce relapses in
alcoholics.

o  Development and testing of selective opioid receptor antagonists for their
effects on alcohol consumption.

3.  THE RENIN-ANGIOTENSIN SYSTEM AND ALCOHOL INTAKE

Alcohol increases plasma osmolality without perturbing cellular osmotic
homeostasis by rapid equilibration across cell membranes.  Thus, single doses
of alcohol induce diuresis and increased plasma volume.  As a consequence,
plasma angiotensin II (AII) levels rise.  Chronic intake of alcohol produces a
comparable effect.  Plasma AII levels are significantly elevated in male rats
fed alcohol for 50 days and significantly rise in actively drinking alcoholic
men a few hours after taking a drink.

Peripheral administration of AII significantly depresses alcohol intake in
animals despite their excessive consumption of water.  In addition, the co-
administration of Losartan (an AII receptor antagonist) partially restores
alcohol intake, but has no effect on water intake in animals.  Interestingly,
ethanol intoxication in the mouse (demonstrated by impaired aerial righting
reflex) was substantially reversed by pre-treatment with Losartan and was
completely abolished by a combination of Losartan and PD123319 (AT1 and AT2
receptor antagonists, respectively). An understanding of the mechanism by
which these AII receptor antagonists abate the behavioral symptomatology of
intoxication would be expected to stimulate development of novel therapeutic
modalities.

Various chemical manipulations known to elevate plasma levels of renin, a
precursor of angiotensin II (e.g., isoproterenol, fluoxetine, prostaglandin
E2, histamine, and inhibitors of angiotensin converting enzyme) likewise
suppress ethanol intake in animals.  NP rats have higher endogenous plasma
renin levels than P rats, and Rapp rats homozygous for a mutant renin gene
drink more alcohol than heterozygotes.  Rats with experimentally induced renal
hypertension develop high plasma renin levels and subsequently drink
significantly less alcohol than sham controls.  Based upon these data, an
inverse relationship exists between plasma AII levels/renin activity and
alcohol consumption (see review by Grupp, 1993).

Further research is needed to gain a better understanding of the role of the
RAS in alcohol consumption. Studies are encouraged to include both genders. 
In addition to the general areas of investigation described above, research is
encouraged (but not limited) to:

o  Understanding the relationship between angiotensin II receptors and alcohol
consumption/intoxification by evaluating levels in selective AII receptor (AT1
vs AT2) knock-out and over-expressing transgenic mice and in animals
overexpressing AII.

o  Clarifying the relationship between angiotensin II and alcohol consumption
(particularly inconsistencies between icv and peripheral administration),
inducible transgenic mice overexpressing AII may be one means to accomplish
this initiative.

4. FOOD INTAKE & ENERGY HOMEOSTASIS: LEPTIN, NPY, AND ALCOHOL INTAKE

Alcohol and food intake are both appetitive and consummatory behaviors.  Thus,
there may be common mechanisms underlying uncontrolled eating and excessive
alcohol intake.  In recent years studies of body weight and energy balance in
animals and humans have identified new peptides and hormones that regulate
food intake. Some of these peptides, including leptin and neuropeptide Y
(NPY), have been shown to modify alcohol consumption.  For example, exogenous
administration of leptin, a peptide which decreases food intake, reduces
voluntary alcohol intake in male C57BL mice by half.  Although NPY is an
extremely potent orixigenic peptide (exogenous administration producing morbid
obesity), C57BL NPY knock-out mice drink substantially more alcohol, and FVB
transgenic mice overexpressing NPY (by 5-fold) drink significantly less
alcohol than their matched controls. The NPY story is made even more
interesting since both the knock-out and transgenic mice described above ate
normal amounts of food and maintained normal body weights, and by the
confirmatory report that P rats have significantly lower levels of NPY in the
brain than NP rats.

Leptin interacts with the arcuate nucleus of the hypothalamus. Leptin up-
regulates proopiomelanocortin (POMC) via alpha-melanocyte stimulating hormone
(alpha-MSH) and its MC-4 receptor, and down regulates both agouti-related
proteins (AGRP) and NPY.  Alpha-MSH down-regulates melanin concentrating
hormone (MCH) in the lateral hypothalamus and diminishes MCH's impact on
various prefrontal cortical sites.  The down-regulation of NPY by leptin
occurs in the paraventricular nucleus, modulating CRF and thyrotropin
releasing hormone (TRH), and impacting upon various sympathetic and
parasympathetic regulatory pathways (see review by Friedman, 1998).

Other peptides have been examined for their effects upon alcohol intake.  The
administration of three peptides (cholecystokinin, bombesin and the
tachykinins) depressed alcohol intake, whereas three others (vasoactive
intestinal peptide, galanin, and beta-endorphin) increased alcohol intake. 
Three were ineffective, including neurotensin, somatostatin, and enterostatin.

Further research is needed to gain a better understanding of the role of food
intake/energy expenditure peptides in alcohol consumption. Studies are
encouraged to include both genders.  In addition to the general areas of
investigation described above, research is encouraged (but not limited) to:

o  Determining whether alcohol consumption is regulated by other proteins and
hormones such as AGRP, MCH, alpha-MSH, cocaine- and amphetamine-regulated
transcript (CART) peptide, and the orexins.

o  Studying alcohol consumption with various rodent models of obesity [e.g.,
models of leptin deficiency such as the obese (ob) mouse, or the diabetic (db)
mouse, which is deficient in the leptin receptor], or available double knock-
out mice (i.e., leptin and NPY).

o  Investigating the apparent discordance between the pharmacologic and
genetic findings involving NPY as they relate to alcohol consumption, food
intake, and weight regulation.

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 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: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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 these policies.

LETTER OF INTENT

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
to:

Peptide 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

APPLICATION PROCEDURES

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 301/435-0714, 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.

BUDGET INSTRUCTIONS

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.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 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 http://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 requested.

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:
http://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:

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

Peptide 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.

REVIEW CONSIDERATIONS

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
methods?

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
support?

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.

AWARD CRITERIA

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
funds.

INQUIRIES

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:

Jules R. Selden, V.M.D., Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD  20892-7003
Telephone:  (301) 443-2678
FAX:  (301) 594-0673
Email:  jselden@willco.niaaa.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

AUTHORITY AND REGULATIONS

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.

REFERENCES

Friedman JM: Leptin, leptin receptors, and the control of body weight.  Nut
Revs 56:S38-S46, 1998.

Froehlich JC: Interactions between alcohol and the endogenous opioid system. 
(S. Zakhari, ed.).  In, Alcohol and the Endocrine System, NIAAA Research
Monograph No. 23, pages 21-35, 1993.

Grupp LA: The renin-angiotensin system as a regulator of alcohol consumption:
a review and some new insights. (S. Zakhari, ed.).  In, Alcohol and the
Endocrine System, NIAAA Research Monograph No. 23, pages 37-65, 1993.

Maickel RP, Sprague JE: Role of ACTH fragments in alcohol consumption. (WA
Hunt and S Zakhari, eds.).  In, Stress, Gender, and Alcohol-Seeking Behavior,
NIAAA Research Monograph No. 29, pages 167-180, 1995.


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