INFECTIOUS CAUSES OF DIARRHEA OR WASTING SYNDROME IN PEOPLE WITH AIDS

NIH GUIDE, Volume 22, Number 45, December 17, 1993



PA NUMBER:  PA-94-019



P.T. 34



Keywords:

  Digestive Diseases & Disorders 

  AIDS 

  0715151 



National Institute of Allergy and Infectious Diseases



PURPOSE



The purpose of this Program Announcement (PA) is to solicit

investigator-initiated applications to identify and determine the

role of opportunistic pathogens as putative causative agents of

diarrhea or wasting syndrome in people with AIDS and to develop

methods for targeted drug discovery against those pathogens.  The

research scope will be limited to studies on parasitic protozoa and

mycobacteria (excluding M. tuberculosis) as causative infectious

agents.  No clinical trials will be supported.



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,

Infectious Causes of Diarrhea or Wasting Syndrome in People with

AIDS, is related to the priority area of HIV infection.  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. 017-001-00474-1) through the Superintendent of Documents,

Government Printing Office, Washington, DC 20402-9325 (telephone

202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, 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.

Applications may be submitted from one institution or may include

arrangements with several institutions if appropriate.  Foreign

institutions are not eligible for First Independent Research Support

and Transition (FIRST) (R29) awards.  Applications from or involving

minority institutions, individuals, and women are encouraged.



MECHANISM OF SUPPORT



Support for this program will be by the investigator-initiated

research project grant (R01) and First Independent Research Support

and Transition (FIRST) award (R29).



RESEARCH OBJECTIVES



Background



Wasting syndrome, a condition that commonly includes chronic

diarrhea, is one of the most frequent AIDS-defining conditions among

adults and adolescents reported to the Centers for Diseases Control

and Prevention.  Although the true incidence of this condition is

unknown, this clinical presentation occurs in a high proportion of

patients with AIDS during the course of the disease.  Severe diarrhea

and weight loss associated with intestinal damage and malabsorption

contribute to malnutrition, poor drug absorption, and diminished

quality of life.  Although diarrhea can often be attributed to

infections with one or more enteric pathogens, no causative agent can

be conclusively identified in up to 50 percent of AIDS patients with

diarrhea.



Intestinal protozoa often associated with AIDS include coccidian

parasites causing protracted diarrhea (e.g., Cryptosporidium parvum

and Isospora belli) and microsporidia (particularly Enterocytozoon

bieneusi, causing intestinal microsporidiosis).  Successful

management of AIDS-associated diarrhea is confounded by the lack of

reproducibly effective therapies; lack of convenient, standardized

diagnostic procedures other than microscopy; lack of quantifiable

assessments of infectious organisms to determine clinical response to

therapy; presence of other concomitant opportunistic infections; and

emergence of new etiologic agents.  Recently, additional

microorganisms have been associated with diarrhea and wasting such as

Cyclospora cayetanensis, a coccidian protozoan causing intractable

diarrhea; Septata intestinalis, an obligate intracellular

microsporidian associated with chronic diarrhea; and Mycobacterium

genavense, an acid-fast bacillus isolated from AIDS patients

exhibiting diarrhea, weight loss and fevers.  Wasting syndrome, in

the absence of diarrhea or gastrointestinal pathogens, is poorly

understood, but may involve decreased nutrient absorption, metabolic

disturbances, and excess production of tumor necrosis factor (TNF) or

other immune effectors.



Objectives and scope



The objective of this PA is to stimulate drug discovery through

original and innovative research focused on key metabolic and

pathophysiologic features of infectious organisms contributing to

diarrhea or wasting syndrome.  Applications based on sound scientific

rationale to improve growth and detection techniques in order to

evaluate therapies against newly recognized pathogens are encouraged.



The research scope will focus on parasitic protozoa and mycobacteria

potentially responsible for causing diarrhea or wasting syndrome.

This includes, but is not limited to, Cryptosporidium, the

Microsporidia species associated with AIDS (Enterocytozoon sp.,

Septata intestinalis), Mycobacterium avium complex, and newly

identified organisms such as Cyclospora cayetanensis, and

Mycobacterium genavense.  Areas of research may include studies

designed to:



o  Develop in vitro (culture) and in vivo (animal model) systems for

drug testing.



o  Develop rapid, noninvasive diagostic methods for the specific and

quantifiable detection of the infectious organism.



o  Determine the interrelation between the etiologic agent and host

factors (e.g., cytokines) contributing to diarrhea or wasting

syndrome.



o  Identify and characterize biochemical, metabolic and molecular

properties of the infectious organism which may serve as targets for

chemotherapy.



o  Discover new therapeutic agents or prophylactic approaches

(chemo-, immuno- or gene-based therapies) through exploitation of

biochemical, metabolic or molecular differences between pathogen and

host.



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 so 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 that 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 should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398

(rev. 9/91) in the Research Plan Sections 1-4 AND summarized in

Section 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, African Americans, Hispanics).

The rationale for studies on single minority population groups must

be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, prevention (and

preventive strategies), diagnosis, or treatment of diseases,

disorders, or conditions.



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 review will be deferred until the information is provided.



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 will be

reflected in the priority score assigned 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.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the receipt dates for

applications for AIDS-related research:  January 2, May 1, and

September 1.  Application kits are available at 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) 435-0714.



Each application must be identified by checking "YES" on line 2a of

the PHS 398 face page, citing this announcement number.



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.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



FIRST (R29) applications must include at least three sealed letters

of reference attached to the face page of the original application.

FIRST applications submitted without the required number of reference

letters will be considered incomplete and will be returned without

review.



REVIEW CONSIDERATIONS



Upon receipt, applications and supporting material will be examined

by the Division of Research Grants for completeness.  Incomplete

applications will be returned without further consideration.



Applications will be assigned on the basis of established Public

Health Service Referral Guidelines.  Applications will be reviewed

independently for scientific and technical merit by study sections of

the Division of Research Grants, NIH in accordance with the standard

NIH peer review procedures.



Review criteria will include:



o  Significance and originality of the research and methodological

approaches.

o  Feasibility of the research and adequacy of the experimental

design.

o  Training, experience, research competence and commitment of the

investigator(s).

o  Adequacy of the facilities and resources.

o  Provisions for the protection of human subjects, the humane care

of animals, and biosafety conditions.



Following scientific and technical merit review, applications will

receive a second level review by the appropriate National Advisory

Council(s).



AWARD CRITERIA



Applications will compete for available funds with all other

applications found to have significant and substantial merit.  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 balance among research areas



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues either to:



Dr. Chris Lambros

Division of AIDS

National Institute of Allergy and Infectious Diseases

Solar Building, Room 2C04

Bethesda, MD  20892

Telephone:  (301) 402-0135

FAX:  (301) 402-3211

E-mail:  cbl@exec.niaid.pc.niaid.nih.gov



Dr. Michael Gottlieb

Division of  Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

Solar Building, Room 3A03

Bethesda, MD  20892

Telephone:  (301) 496-7115

FAX:  (301) 402-0804

E-mail:  mog@exec.niaid.pc.niaid.nih.gov



Direct inquiries regarding fiscal matters to:



Ms. Jane Unsworth

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B22

Bethesda, MD  20892

Telephone:  (301) 496-7075

FAX:  (301) 480-3780



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No 93.856, Microbiology and Infectious Diseases Research.

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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