Full Text PA-97-062
NIH GUIDE, Volume 26, Number 18, May 30, 1997
PA NUMBER:  PA-97-062
P.T. 34


National Institute on Alcohol Abuse and Alcoholism
National Institute on Aging
National Institute of Diabetes and Digestive and Kidney Diseases
The National Institute on Alcohol Abuse and Alcoholism (NIAAA)
invites applications to investigate how alcohol-induced hormonal
changes can lead to medical complications. Alcohol intake can
influence the synthesis, secretion, and action  of many hormones
resulting in physiological and pathological disturbances.  Either
blunting or overstimulation of hormonal activities can disturb
intercellular signaling and create adverse consequences.  For
example, alcohol-induced hormonal changes are associated with
pancreatitis, perturbed alcohol metabolism and associated liver
injury, osteoporosis, immune system impairment, and impaired
fertility. Studies are encouraged to establish cause-and-effect
relationships and to clarify the biochemical and molecular mechanisms
by which alcohol influences the synthesis, secretion and action of
various hormones.  Also, studies are encouraged to interpret the
mechanisms of interactive effects of alcohol and hormones which may
cause tissue injury. Such studies will provide information that can
be used to ameliorate alcohol-hormone-related medical complications.
The National Institute on Aging (NIA) is interested in research
applications examining how alcohol use influences the development of
age-related changes in the endocrine system.
The Endocrinology Research Programs at the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), in particular,
are interested in studies which focus on hormonal regulation of gene
expression under normal and pathological conditions, including
alcohol-induced altered conditions of hormonal release and response.
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 program
announcement is related to the priority area of reducing the medical
complications 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, D.C. 20402-9325 (telephone 202-512-1800).
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) Awards (R29).
Research support may be obtained through applications for a research
project grant (R01) or First Independent Research Support and
Transition (FIRST) Award (R29).  Applicants may also submit
Investigator-Initiated Interactive Research Project Grants (IRPG)
under this program announcement.  Interactive Research Project Grants
require the coordinated submission of related regular research
project grant applications and, to a limited extent, FIRST Award
applications from investigators who wish to collaborate on research,
but do not require extensive shared physical resources.  Further
information on the IRPG mechanism is available in program
announcement PA-96-001, NIH Guide for Grants and Contracts, Vol. 24,
No. 35, October 6, 1995, and from the program staff listed under
INQUIRIES at the end of this announcement. The FIRST Award and IRPG
program announcements are also available on the NIAAA Home Page at
http://www.niaaa.nih.gov. Program project grant applications (P01)
will not be accepted for this announcement. Investigators who wish to
submit an application that requests more than $500,000 for direct
costs in any one year must contact program staff prior to submitting
an application.
Examples of important research on consequences of alcohol-induced
hormone disorders include, but are not limited to the following:
1.  Alcoholic Liver Disease (ALD):
Despite recent advances in our understanding of ALD, it remains a
major cause of mortality and morbidity in this country. Of the 25,407
people who died of cirrhosis in this country in 1992, at least 11,868
deaths were due to alcoholic cirrhosis (NIAAA, 1996). Alcohol-induced
liver damage occurs not only from exposure to high blood alcohol
concentrations in the portal circulation, but also from toxic
metabolites generated by alcohol metabolism. The metabolism of
alcohol is known to generate reactive oxygen intermediates (ROI)
which have been implicated in the genesis of ALD. In addition,
alcohol metabolism is influenced by a number of hormones. For
example, the activity of liver alcohol dehydrogenase (ADH) is
influenced by growth hormone (GH), testosterone,  thyroid hormones,
and glucocorticoids (Mezey et al., 1993), the plasma levels of which
are affected by alcohol.  Also, GH, known to be influenced by alcohol
intake, was shown to regulate the production of CYP2E1 in hepatic
microsomes (Chen et al., 1995). Whether alcohol-induced hormone
alterations  can significantly  influence the course of liver injury
via modulating the activities of ADH and CYP2E1 and subsequent
alcohol metabolism needs investigation.  Women are more susceptible
than men to alcohol-induced liver injury (NIAAA, 1993) which could be
due in part to the effects of estrogen.  Estrogen has recently been
shown to sensitize Kupffer cells to LPS leading to increased
production of NO and TNF,  known mediators of liver injury (Ikejima
et al., 1996). The role of alcohol-induced changes in sex hormones in
the susceptibility to  liver injury needs clarification.
2.  Pancreatitis:
Chronic alcohol abuse is associated with 70 to 80 percent of cases of
chronic pancreatitis in this country (Serles et al., 1989), affecting
about 100,000 people annually. This condition can lead to
maldigestion, diabetes, and pancreatic cancer. Animal studies suggest
that premature activation of pancreatic enzyme precursors within the
pancreas itself injures the tissue by autodigestion, triggering the
process of pancreatitis. Chronic alcohol intake increases the
activity of pancreatic proteolytic enzymes (Ponnappa et al., 1990).
Several studies suggest that the intestinal hormone cholecystokinin
(CCK)  is associated with alcohol-induced pancreatitis.  In rats,
both intragastric and intravenous infusions of alcohol increase by
several-fold the plasma levels of CCK ( Liddle et al., 1984; Saluja
et al., 1993), a hormone known to stimulate pancreatic enzymes. In
addition, a CCK analogue (caerulin) induces pancreatitis in
experimental animals (Saluja et al., 1987). Furthermore, alcohol-fed
rats were  more susceptible than control rats to the development of
caerulin-induced pancreatitis (Quon et al., 1991). Studies are
required to elucidate the molecular and biochemical mechanisms by
which alcohol stimulates the synthesis and/or  secretion of CCK from
the intestinal epithelial cells.
3.  Osteoporosis:
Chronic heavy alcohol intake is associated with decreased bone
mineral density, increased bone loss, and increased risk for  bone
fractures (Bikle, 1993; Griffiths et al., 1993). An estimated 20-25
million Americans are afflicted with osteoporosis, resulting in an
estimated 1.5 million fractures each year (Peck et al., 1988).
Adverse effects of alcohol on bone appear to be direct as well as
indirect. Alcohol directly inhibits the proliferation and function of
the bone forming cells, osteoblasts (Chavassieux et al., 1993) and
increases the activity of the bone resorbing cells, osteoclasts
(Cheung et al., 1995).  In addition, alcohol can influence the plasma
levels of various hormones which play important roles in the bone
remodeling process. For example, chronic alcohol consumption can
depress plasma levels of testosterone (Mendelson et al., 1978),
required for maintaining bone mineral density in males  (Rosen et
al., 1995).
In women, estrogens  are required for maintaining bone integrity as
observed by the increased incidence of osteoporosis in postmenopausal
women. Surprisingly, moderate alcohol consumption in postmenopausal
women is associated with increased plasma levels of estradiol (Tivis
and Gavaler, 1994), a hormone commonly used to prevent bone loss in
postmenopausal women. Furthermore, both moderate  (Laitinen et al.,
1991) and heavy (Felson et al., 1995) alcohol intake were associated
with increased bone mineral density in postmenopausal women. In
contrast, in premenopausal women, alcohol consumption was not
associated with increased plasma estrogens levels (Dorgan et al.,
1994), and there was a negative correlation between alcohol intake
and axial bone mineral density (Stevenson et al., 1989).  Alcohol
also influences plasma levels of other hormones which regulate the
bone remodeling process, such as GH, glucocorticoids, parathyroid
hormone, vitamin D3, and calcitonin. It is important to understand
the mechanisms  of hormone-mediated effects of alcohol on bone
formation and bone resorption.
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 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 20, 1994 (FR 59 14508-14513) and reprinted
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.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone 301/435-0715, E-mail:
asknih@odrockm1.od.nih.gov.  The title and number of the program
announcement must be typed in section 2 on the face page of the
application. 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 of reference letters will be considered
incomplete and will be returned without review.
The completed original application and five legible copies must be
sent or delivered to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer 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 the applications under review will be discussed, assigned a
priority score, and receive a second level review by the appropriate
national advisory council.
Review Criteria
Criteria to be used in the scientific and technical merit review of
alcohol research grant applications will include 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.  When applicable, the adequacy of procedures to protect or
minimize effects on animal and human subjects and the environment.
7.  When applicable, compliance with NIH policy on inclusion of women
and minorities in research involving human subjects.
The review criteria for FIRST Awards (R29) are contained in the FIRST
program announcement (revised August 1996).
Applications will compete for available funds with all other approved
applications.  Applications approved by the appropriate National
Advisory Council will be considered for funding on the basis of the
overall scientific and technical merit of the application as
determined by peer review, programmatic needs and balance, and the
availability of funds.
The opportunity to clarify any issues or questions from potential
applicants is welcome.
Direct inquiries regarding scientific aspects of proposed research
Vishnudutt Purohit,  Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4224
FAX:  (301) 594-0673
Email: vpurohit@willco.niaaa.nih.gov
Jules Selden, V.M.D., Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-2678
FAX:  (301) 594-0673
Email:  jselden@willco.niaaa.nih.gov
Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  bellinof@gw.nia.nih.gov
Ronald N. Margolis, Ph.D.
Endocrinology Section
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-12J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email:  rm76f@nih.gov
Direct inquiries regarding fiscal matters to:
Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov
Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  pikeb@gw.nia.nih.gov
Kim Law
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AS-49A
Bethesda, MD  20892-6600
Telephone:  (301) 594-8869
This program is described in the Catalog of Federal Domestic
Assistance, Nos. 93.273 (NIAAA), 93.866 (NIA), and  93.847 (NIDDK).
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
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.
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73:53-79, 1993
Chavassieux P, Serre CM, Vergnaud P, Delmas PD, Meunier PJ: In Vitro
evaluation of dose effects of ethanol on human osteoblastic cells.
Bone Mineral 22:95-103, 1993
Chen G, Ronis MJ, Badger TM: Pituitary Regulation of rat hepatic
microsomal CYP2E1. Toxicologist 15:113, 1995
Cheung RCY, Gray C, Boyde A, Jones SJ: Effects of ethanol on bone
cells in vitro resulting in increased resorption. Bone 16:143-147,
Dorgan JF, Reichman ME, Judd JT, Brown C: The relationship of
reported alcohol ingestion to plasma levels of estrogens and
androgens in premenopausal women. Cancer Causes Control 5:53-60, 1994
Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP: Alcohol intake and
bone mineral density in elderly men and women. Am J Epidemiol
142:485-492, 1995
Griffiths HJ, Parantainen H, Olson P: Alcohol and bone disorders.
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Keith LD, Crabbe JC, Robertson LM, Kendall JW: Ethanol stimulated
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Laitinen KL, Valimaki M, Keto P: Bone mineral density measured by
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cholecystokinin in rats: effects of food, trypsin inhibitor, and
alcohol. Gastroenterology 87:542-549, 1984
MacGregor RR: Alcohol and immune defense. JAMA 256:1474-1479, 1986
Mendelson JH, Ellingboe J, Mello NK, Kuehnle J: Effects of alcohol on
plasma testosterone and luteinizing hormone levels. Alcohol Clin Exp
Res 2:255-258, 1978
Mezey E, Potter JJ, Yang VW: Hormonal regulation of the rat class I
alcohol dehydrogenase. Alcohol Alcohol Suppl 2:57-62, 1993
NIAAA: Alcohol and Health. Eighth Special Report to the U.S.
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Peck WA, Riggs BL, Bell NH, Wallace RB, Johnston CC, Gordon SL:
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Ponnappa BC, Hoek JB, Jubinski E: Ethanol withdrawal stimulates
protein synthesis in rat pancreatic lobules. Biochem Biophys Acta
1036:107-112, 1990
Quon MG, Kugelmas M, Wood RL, Chandrasoma P, Valenzuela JE: Cellular
events of caerulin-induced pancreatitis in alcoholic rats.
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Redei E, Branch BJ, Taylor AN: Direct effect of ethanol on
adrenocorticotropin (ACTH) release in vitro. J Pharmacol Exp Ther
237:59-64, 1986
Rivier C, Bruhn T, Vale F: Effect of ethanol on the
hypothalamic-pituitary-adrenal axis in the rat: Role of
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Rivier C: Alcohol stimulates ACTH secretion in the rat: mechanisms of
action and interactions with other stimuli. Alcohol Clin Exp Res
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Rosen HN, Tollin S, Balena R, Middlebrooks VL: Bone density is normal
in male rats treated with finasteride. Endocrinology 136:1381-1387,
Saluja A, Hashimoto S, Saluja M, Powers RE, Meldolesi J, Steer ML:
Subcellular redistribution of lysosomal enzymes during
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Saluja A, Maitre N, Runzi M, Saluja M, Dawya R, Nishino H, Steer ML:
Ethanol-induced increase in plasma cholecystokinin level mediated by
the release of CCK-releasing into the duodenum. Gastroenterology
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Sarles H, Bernard JP, Johnson C, Chir M: Pathogenesis and
epidemiology of chronic pancreatitis. Ann Rev Med 40:453-468, 1989
Stevenson JC, Lees B, Davenport, M, Cust MP, Ganger RF: Determinants
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