Full Text DK-94-006

THE PATHOGENESIS OF WASTING IN AIDS

NIH GUIDE, Volume 22, Number 37, October 15, 1993

RFA:  DK-94-006

P.T.


Keywords: 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 21, 1994
Application Receipt Date:  March 31, 1994

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research grant applications to
investigate the pathogenesis of wasting syndromes in acquired immune
deficiency syndrome (AIDS) and to develop new approaches for the
prevention or reversal of wasting in AIDS.  Applications will be
encouraged for both basic science and clinical experiments that will
provide direction for future treatment.

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 Request
for Applications (RFA), The Pathogenesis of Wasting in AIDS, is
related to the priority areas of HIV infection and nutrition.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or Healthy People 2000" (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.
Minority individuals and women are encouraged to submit as Principal
Investigators.  Foreign institutions are not eligible for First
Independent Research Support and Transition (FIRST) awards (R29).

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 should be included
with the application.

MECHANISM OF SUPPORT

Support of this program will be through the NIH research project
grant (R01) or FIRST (R29) awards.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  Except as otherwise stated in this announcement,
awards will be administered under PHS grants policy as stated in the
PHS Grants Policy Statement.

This RFA is a one-time solicitation.  Generally, future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.  The total requested project period
for applications submitted in response to this RFA may not exceed
four years.  A maximum of three years may be requested for foreign
awards.  The earliest possible award date will be September 30, 1994.

FUNDS AVAILABLE

For FY 1994, $2,500,000 will be committed to fund applications
submitted in response to this RFA.  It is anticipated that up to 12
awards will be made.  However, this funding level is dependent upon
the receipt of a sufficient number of applications of high scientific
merit.  Applicants must limit their requests to not more than
$160,000 direct costs for the initial budget period.  Although this
program is provided for in the financial plans of the NIDDK, the
award of grants pursuant to this RFA is also contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Involuntary weight loss or wasting indicative of severe protein
energy malnutrition is a frequent complication of acquired immune
deficiency syndrome (AIDS) and may significantly contribute to the
progression of AIDS including death.  Mortality from wasting appears
to be related to the magnitude of tissue depletion and losses in lean
body cell mass and restoration of body cell mass may enhance
survival.  These losses in AIDS patients are out of proportion to
losses of total body weight or fat.  While weight loss is variable
and occasionally reversible with the treatment of underlying
infections and/or easily identifiable reversible causes, the majority
of patients do not respond to conventional interventions.

The mechanism(s) of weight loss in AIDS has not been clearly
elucidated.  The etiology is likely to be multifactorial, the result
of interactions between decreased caloric intake, malabsorption, and
altered energy utilization or expenditure secondary to infection,
hormonal and/or metabolic abnormalities.  There is already evidence
of perturbations in lipid metabolism, cytokine response, and
energy/nitrogen balance in the AIDS wasting syndrome as well as
indications of gastroenterologic dysfunction from infection or
inflammatory cytokines.

A number of hormones and cytokines have been implicated in the
pathophysiology of HIV-related anorexia/cachexia.  Cytokines, such as
interleukin-1 (IL1), tumor necrosis factor (TNF), and interferons
(IFN) can suppress appetite and disturb normal metabolic activity.
HIV wasting syndrome has been associated with inappropriately
increased hepatic lipogenesis, hypertriglyceridemia and
hypermetabolism with increased resting energy expenditure (REE).
There is significant correlation between circulating interferon alpha
levels and both triglyceride clearance and de novo hepatic
lipogenesis (r=.8).  Increased de novo hepatic lipogenesis is an
inappropriate and energy wasting response to weight loss.

Alimentary impairment is a frequent cause of wasting and occurs when
primary or secondary intestinal changes result in decreased
intestinal surface area, defects in the mucosal function, or rapid
cell turnover producing immature epithelium.  Such impairments are
frequently associated with idiopathic diarrhea in AIDS patients.
Hampered nutrient absorption may also be a complication of the
systemic effects of hepatitis, lymphoma or Kaposi sarcoma.  Partial
villus atrophy, crypt hyperplasia, or increased numbers of
intraepithelial lymphocytes suggest microbial or immune mediated
intestinal damage may be important factors in AIDS enteropathies and
malabsorption.  Intestinal injury or damage from protozoal,
parasitic, bacterial, or viral infections can result in significant
functional impairment.  These pathogens include cytomegalovirus,
candida, cryptococcus, cryptosporidium, isospora and mycobacterium
avium-intracellularae (MAI).

Total parenteral nutrition has had variable effects on body
composition in AIDS wasting syndrome (AWS), with tissue repletion
occurring in patients with eating disorders or malabsorption
syndromes and progressive depletion occurring in patients with
serious systemic infections.  Enteral nutrition also can replete body
mass in AIDS patients without severe malabsorption.  Both modalities
support the concept that adequate nutrition has an essential role in
the management of AIDS.

Pharmacologic stimulation may provide another means to promote weight
gain.  There is evidence that hormones, such as growth hormone,
progestational agents, growth factors, cytokines and/or factor-
cytokine antagonists may have a role in the therapy of AWS.
Megestrol acetate, a synthetic, orally active progestational agent,
has been reported to stimulate appetite and improve caloric intake.
There is evidence that growth hormone administration may produce
improved nitrogen balance.  The results of these studies indicate
that hormonal therapy or nutritional support can improve the
physiologic status of selected AIDS patients.  Clearly, further
understanding of the role of hormones, growth factors, cytokines, and
other endocrine factors in AIDS wasting syndrome, within normal and
HIV infected tissue is required.  The precise roles, interactions and
contributions of these factors need further definition.  The
prospects for clinical application of these substances in the
treatment of AIDS magnifies this imperative.

Scope

Some examples of research topics that would be considered responsive
to this solicitation include:

o  evaluation of body composition, hormonal/growth factor/cytokine
secretion, alimentary histopathology, lipid metabolism, caloric
intake, nitrogen balance, metabolic rates, and potential therapies in
animal models of AIDS

o  the hormonal regulation of growth factors, cytokines or their
receptors and their roles as mediators of wasting in HIV infected
individuals

o  evaluation of potential therapies for AWS including hormonal
interventions and their effects on body composition, basal metabolic
rate, lipolysis/lipogenesis, resting energy expenditure, and
lipoprotein levels in HIV infected patients or animal models of AIDS

o  evaluations of synergies or antagonisms among growth factors or
cytokines that may be important in the alterations of appetite,
lipid, protein or carbohydrate metabolism

o  approaches to the correction of anorexia or metabolic/endocrine
aberrations with hormones, growth factors, cytokines or their
antagonists

o  evaluation of body composition in the setting of asymptomatic and
symptomatic HIV infection with emphasis on potential mechanisms
involved in patient progression to wasting

o  assessment of metabolic parameters, such as hepatic lipogenesis
and REE, in asymptomatic and symptomatic HIV infection

o  measurement of adaptive mechanisms to conserve lean body mass in
the setting of asymptomatic and symptomatic HIV infection

o  evaluation of various nutritional interventions during the early
phases of HIV infection with special emphasis on the impact of such
interventions on overall disease process and the efficacy of single
versus combined nutritional modalities

o  mechanisms involved in intestinal malabsorption including
mechanisms of malabsorption in intestinal infection in AWS

o  the regulation of the production and gene expression of
gastrointestinal neuropeptides, hormones and cognate receptors in
AIDS and HIV infected cells and tissues

o  the development of new or improved approaches to define the
etiology of intestinal dysfunction in HIV infection which may lead to
improved diagnosis and treatments

These areas of interest are not listed in any order or priority.
They are only suggested examples of areas of research.  Applicants
are encouraged to propose other areas that are related to the
objectives and scope described above.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations go that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample is appropriate for the scientific objectives of the
study.  This information must be included in the form PHS 398 (rev.
9/91) in Item 4 (Research Design and Methods) of the Research Plan
AND summarized in Item 5, Human Subjects. Applicants are urged to
assess carefully the feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes that it
may not be feasible or appropriate in all research projects to
include representation of the full array of United States
racial/ethnic minority populations; i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders,
Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 21, 1994, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) must be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  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 check the YES box.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

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

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by March 31, 1994.  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 announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  However, it is
allowable to submit the same project as both an R01 and as a
component project of a program project, with the proviso that only
one could be funded.  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 previously
reviewed.  Such applications must not only include an introduction
addressing the previous critique but also be responsive to this RFA.

FIRST Award (R29) applications 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be initially reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK staff function.  If the application is not responsive
to the RFA, NIDDK staff will contact the applicant to determine
whether it should be returned to the applicant, or held until the
next regular receipt date and reviewed in competition with all other
applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.  If
the number of applications is large compared to the number of awards
to be made, a preliminary scientific peer review may be conducted and
applications withdrawn from further competition when they are not
competitive for the award.  The NIDDK will notify the applicant and
institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA.  Following this review, the applications will be given
a second level review by the NIDDK Advisory Council unless not
recommended for further consideration by the initial review group.

Review criteria for RFAs are generally the game as those for
unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

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 resources necessary to perform the research;

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

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

o  for foreign applications: uniqueness of research such that it can
be performed only outside of the United States.

AWARD CRITERIA

Funding decisions will be made based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

W. Lorenzo Jackson, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 594-7576
FAX:  (301) 594-9011

Inquiries regarding fiscal matters may be directed to:

Ms. Kim Law
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649D
Bethesda, MD  20892
Telephone:  (301) 594-7543

Schedule

Letter of Intent Receipt Date:  February 21, 1994
Application Receipt Date:       March 31, 1994
Initial Review:                 June 1994
Second Level Review:            September 1994
Anticipated Date of Award:      September 30, 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.847.  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.

.

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