Full Text PA-95-079

PATHOPHYSIOLOGY OF ANOREXIA IN DISEASE AND AGING

NIH GUIDE, Volume 24, Number 27, July 28, 1995

PA NUMBER: PA-95-079

P.T. 34

Keywords: 
  Pathophysiology 
  Aging/Gerontology 
  0715091 


National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Deafness and Other Communication Disorders
National Institute on Aging
National Institute of Child Health and Human Development
National Institute of Allergy and Infectious Diseases
National Institute of Mental Health

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), the National Institute on Deafness and Other Communication
Disorders (NIDCD), National Institute on Aging (NIA), National
Institute of Child Health and Human Development (NICHD), National
Institute of Allergy and Infectious Diseases (NIAID), and National
Institute of Mental Health (NIMH) are interested in receiving
research grant applications for support of research on
pathophysiologic mechanisms that mediate the loss of appetite seen in
disease and in aging.  Applications covering a broad range of
activities in this area, including both basic and clinical research,
are encouraged.  This program announcement (PA) is issued in order to
encourage investigator-initiated research projects in these areas of
special programmatic interest.  This PA complements an existing NIMH-
sponsored PA, Anorexia Nervosa and Bulimia Nervosa:  Basic Brain,
Behavioral, and Clinical Studies (PA-91-79) by its coverage of
appetite disturbance phenomena without restriction to currently
defined psychiatric disorders of anorexia nervosa and bulimia
nervosa.

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 national activity for setting priority areas.  This PA,
Pathophysiology of Anorexia in Disease and Aging, is related to the
priority area of nutrition.  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).

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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be by research project grant (R01) and
FIRST awards (R29).  Because the nature and scope of the research
proposed in response to this PA may vary, it is anticipated that the
size of award will vary also; however, the average size of grants
funded by NIDDK is estimated to be approximately $200,000, total
costs.

RESEARCH OBJECTIVES

This program announcement is intended to stimulate research on
pathophysiologic mechanisms leading to loss of appetite, which is
observed in association with many disorders, including AIDS; end-
stage cardiac, renal, and liver disease; cancer; tuberculosis; and
major depressive disorder.  Appetite disturbances may also be
reported among individuals with anorexia nervosa and bulimia nervosa.
In children, loss of appetite associated with many chronic disorders
or infections often impedes normal growth.  Loss of appetite is also
commonly observed in the elderly.  While there has been a great deal
of interest in the understanding of cachexia, wasting is a result of
a number of factors, including decreased energy intake,
malabsorption, and increased energy utilization.  Little research has
been conducted investigating the causes of loss of appetite that
contribute to this end result.  Further understanding of the
metabolic and physiologic bases for anorexia could lead to improved
means of preventing the secondary wasting and other consequences of
poor nutritional status, such as depressed immune function,
associated with these conditions.  Improved understanding of the
mechanisms leading to loss of appetite in chronic disease or in some
elderly persons may have profound implications for understanding
anorexia associated with other illnesses, or for intervening in
dysregulation of eating behavior in other disorders, such as bulimia
nervosa, binge eating disorder, and obesity.

Anorexia appears to be the end-result of a modification of central
regulation of feeding behavior.  It can occur as a distinct symptom
or as part of a cluster of behavioral and motivational symptoms as in
the syndrome of depression.  There is some indication that aging
results in impairment in ability to control food intake following
underfeeding in both humans and animals, which can result in
decreased energy intake and weight loss among the elderly.  In
addition, decreased food intake is associated with certain
alterations of smell and taste function.  A number of physiologic
changes have been noted in loss of appetite in humans and animals,
although it is often difficult to differentiate primary from
secondary phenomena.

In animal studies, loss of appetite has been associated with
increased brain tryptophan and serotonin levels.  Observations of
elevated levels of brain tryptophan and serotonin may be a partial
explanation for the development of loss of appetite in patients with
chronic liver disease or chronic renal failure.  In fact, some of the
therapeutic interventions for these diseases have been developed to
minimize the availability of nutrients that could be metabolized to
tryptophan and serotonin (i.e., branched-chain amino acid therapy).

The role of deficiencies of micronutrients such as zinc in causing
anorexia in both animal models and humans is inconclusive.  Tumor-
bearing rats have also been found to have decreased hypothalamic
neuropeptide Y (NPY), a neurotransmitter that increases nutrient
intake, particularly intake of carbohydrate.  Elderly humans also
have been found to have low cerebrospinal fluid (CSF) and plasma
levels of beta endorphins compared with younger controls, and also
show differences in amino acid concentrations in the CSF.  The role
of corticotropin releasing hormone (CRF) in the loss of appetite
associated with disease and aging also deserves exploration.  Other
neural and/or hormonal factors, such as cholecystokinin (CCK) and
corticotropin (ACTH), have also been hypothesized to play a causative
role in loss of appetite in diseases ranging from AIDS to chronic
liver disease.  Nutrient intake may play a role in modulating these
factors, such as a relationship found in animals between chronic
ethanol consumption and sensitivity to the anorectic effects of
CCK-8.  Novel substances, such as a glycoprotein found in Mung bean
sprouts, have been found to reduce food intake in animals.

With increased knowledge about the mechanisms leading to the
development of loss of appetite, specific therapeutic interventions,
such as the use of pharmacologic agents, food flavor enhancement, or
dietary manipulation, could be considered.  Since anorexia is also
associated with early satiety, a major factor contributing to reduced
food intake, it is likely that innovative approaches to control food
intake could be achieved.  Better understanding of factors
responsible for early satiety might allow the development of
therapeutic approaches to prevent and treat obesity and other eating
disorders.

Specific examples of research topics appropriate for inclusion in
applications responsive to this program announcement include, but are
not limited to:

o  Studies characterizing primary endocrine, metabolic, cellular and
related pathophysiologic mechanisms that contribute to loss of
appetite in disease, aging or associated with use of certain
medications.  This includes determination of the potential role of
peptides, neurotransmitters, hormones, and cytokines in the
development or maintenance of loss of appetite

o  Studies investigating neural function and networks within the
neural system (using a variety of probes or assessment techniques,
such as brain imaging, cognitive testing, etc.) related to the
anorexia of disease and/or aging

o  Studies on the role of alterations in olfaction and gustation in
anorexia associated with disease and/or aging

o  Studies on the association of anorexia with other motivational,
behavioral, affective, and cognitive factors or symptoms

o  Studies of molecular mechanisms in the infection process and host
defense that lead to the initiation, maintenance, and/or exacerbation
of the anorectic state observed in chronic infectious diseases such
as AIDS and tuberculosis

o  Studies on the role of factors such as vagal tone and gastric
motility on early satiety in loss of appetite

o  Studies of the role micronutrient and/or macronutrient
deficiencies or excesses in the development or maintenance of loss of
appetite

o  Studies of specific taste and smell aversions in loss of appetite

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 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 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.

APPLICATION PROCEDURES

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.  The receipt dates for
applications for AIDS-related research are found in the PHS 398
instructions.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda MD
20892-7762, telephone 301/435-0714.  The title and number of the
program announcement must be typed in item 2 on the face page of the
application.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
with the application.

The completed original application and five legible copies must be
sent or delivered to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Applications for FIRST awards (R29) must include at least three
letters of reference attached to the face page of the original
application.  Applications submitted without the required number of
reference letters will be considered incomplete and will be returned
without review.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit in accordance with the standard NIH peer review
procedures.  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 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

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  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.

The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment.

o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or which provide augmentation of
existing U.S. resources.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications assigned to the relevant Institute.  The following will
be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review o
Availability of funds
o  Program  priority.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Susan Z Yanovski M.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive,  Room 6AN-18 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8882
FAX:  (301) 480-8300
Email:  yanovskis@niddkep.nih.gov.

Jack Pearl, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders 6120
Executive Boulevard, Room 400-C - MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3464
FAX:  (301) 402-6251
Email:  Jack_Pearl@nih.gov

Pamela E. Starke-Reed, Ph.D.
Office of Nutrition
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-4603
FAX:  (301) 402-0010
Email:  PS39P@NIH.GOV

Gilman Grave, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development 6100
Executive Boulevard, Room 411B - MSC 7510
Bethesda, MD  20892-7510
Email:  graveg@hd01.nichd.nih.gov

Eugene M. Zimmerman, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A42
Bethesda, MD  20892
Telephone:  (301) 496-8973
FAX:  (301) 402-2571
Email:  ez1b@nih.gov

Matthew V. Rudorfer, M.D.
Clinical Treatment Research Branch
National Institute of Mental Health
5600 Fishers Lane, Room 18-105
Rockville, MD  20857
Telephone:  (301) 443-4527
FAX:  (301) 443-6000
Email:  mr118r@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ms. Sharon Bourque
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AS-49H - MSC 6600
Bethesda, MD  20982-6600
Telephone:  (301) 594-8846
Email:  bourques@ep.niddk.nih.gov

Mr. Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B35
Bethesda, MD  20892
Telephone:  (301) 496-7075
Voicemail:  (301) 402-5512
FAX:  (301) 480-3780
Email:  tb22i@nih.gov

Mr. E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development 6100
Executive Boulevard, Room 411B - MSC 7510
Bethesda, MD  20892-7510
Email:  shawverd@hd01.nichd.nih.gov

Ms. Sharon Hunt
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders 6120
Executive Boulevard, Room 400-B - MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email:  sh79f@nih.gov

Ms Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-3065
Email:  dt21a.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.848.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 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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