STUDIES ON ENVIRONMENTAL TOXICANTS AND THE IMMUNE SYSTEM

NIH GUIDE, Volume 23, Number 11, March 18, 1994



PA NUMBER:  PA-94-049



P.T. 34



Keywords:

  Immune System 

  Environmental Effects 



National Institute of Environmental Health Sciences

National Institute of Allergy and Infectious Diseases



PURPOSE



The National Institute of Environmental Health Sciences (NIEHS) and

the National Institute of Allergy and Infectious Diseases (NIAID)

announce their interest in receiving individual research grant

applications for support of studies on the interactions between

environmental substances and their effects on immune function, which

last appeared in the NIH Guide, Vol. 20, No. 23, June 14, 1991, Page

5.  The objective is to promote research at the molecular and

cellular level to better understand mechanisms of

environmentally-induced aberrations within the immune system in order

to gain insight into approaches to mitigate the effects of such

agents.  These agents are substances that may be present in the

natural environment or have been added by human activities and are

known to or are suspected of inducing illnesses that affect or

involve the immune systems.



The NIAID is the principal agency that supports fundamental research

concerned with the structure and function of the immune system in

health and disease.  The acquisition of new and deeper knowledge

about the immune system is requisite to the development of improved

procedures for prevention, diagnosis and treatment of immunological

diseases and of diseases having a major immunological component.  The

interest of the NIAID in environmental toxicology is predicated on

the strong likelihood that the analysis of interactions between

noxious substances in the environment and the immune system can

provide insight, from a largely-ignored perspective, on some of the

typical functions of the immune system, the adaptability and

plasticity of the immune system, and the susceptibility of the immune

system to abnormalities induced by chemical and physical insult.



The NIEHS is the principal Federal funding agency for support of

basic research on environmental factors that contribute to human

health problems and disease.  Major emphasis by NIEHS is placed upon

research examining those physical and chemical substances resulting

from industrial progress.  However, there also are many natural

environmental substances which have been found to have deleterious

effects on human health and are within the purview of the NIEHS

mission.  Many of these substances cause human health problems by

disrupting normal immune function which can lead to a disease state.



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,

Studies on Environmental Toxicants and the Immune System, is related

to the priority area of environmental health.  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 or local

governments, and eligible agencies in the Federal government.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.  Applications from

minority individuals and women are encouraged.



MECHANISM OF SUPPORT



This PA will use the National Institutes of Health (NIH) individual

research grant (R01) and FIRST (R29) award.  Responsibility for

planning, direction, and execution of the proposed project will be

solely that of the applicant.



RESEARCH OBJECTIVES



The effects of environmental toxicants may be divided into three

broad categories: suppression/inhibition of immunological competence;

initiation or triggering of autoimmunity; and stimulation of

allergic/hypersensitivity reactions.  Although the NIEHS and NIAID

have overlapping interests with respect to each of these categories

of effect, it is reasonable to state that the interests of NIEHS

center on the effects of chemical/physical agents that suppress or

reduce the capacity of the immune system.  The interests of NIAID are

more focussed on the actions of chemical/physical agents that

precipitate or lead to autoimmune and allergic disorders.  NIEHS's

interests are to identify and characterize the mechanisms of action

of substances that affect the immune system and to determine the

magnitude and consequences of exposure to such substances.  NIAID is

concerned with understanding the immuno-physiological processes that

are affected by environmental agents and elucidating the pathogenesis

of the disorders that they cause.  Both Institutes are interested in

approaches that may mitigate the noxious effects of environmental

agents and in the development of improved animal and in vitro models

for studying the effects of noxious substances.



Research Goals and Scope



These applications should emphasize mechanisms rather than mere

descriptions of processes.  They should utilize state-of-the-art

immunology, biochemistry, and molecular biology in such

investigations.



The following are examples of projects/topics that would be of

interest but are not meant to present the full range of

possibilities:



o  Determine the mechanisms by which toxicants affect individual

components of the immune system; e.g., on cellular components such as

antigen-processing cells (APC), B- lymphocytes and T-lymphocytes.



o  Identification of the actual immunogenic components (fragments,

molecular conjugates, etc.) and epitopes of toxicants that trigger

allergic/hypersensitive responses or autoimmunity, and detailed

analyses of their processing by APC and presentation to T- and

B-cells.



o  Development of in vitro systems for systematic quantitative

analyses and mechanisms of action of toxicants on individual cellular

components of the immune system: APC, B-cells and T-cells.



o  Comprehensive studies on toxicant-induced allergic/hypersensitive

responses designed to reveal the roles of components such as T-cells,

APC, IgE-producing B- cells, IgE molecules, leukocytes and mediator

substances in the development and manifestation of those responses.



o  Development of approaches to prevent or reduce the undesirable

effects of toxicants on the immune system; e.g., appropriate

pre-immunization ("vaccination") against toxicants or preparation of

monoclonal antibodies capable of nullifying the effects of toxicants.



o  Evaluation of the effects of "natural" levels of toxins on the

immune system.



o  Studies on the genetics of susceptibility and resistance to the

effects of toxic substances.



o  Studies on the genetic control of susceptibility and resistance to

those effects of toxicants that lead to autoimmune or allergic

disorders.



o  Studies on the pharmacologic control of susceptibility of the

immune system to toxic substances.



o  Studies on dual effects of toxic agents such as simultaneous

inactivation of certain components of the immune system and

activation of other components.



o  Studies on toxicant-triggered expression of stress proteins (e.g.,

heat-shock proteins) and special receptors such as those for aromatic

hydrocarbons controlled by the "Ah" genetic locus and found in

leukocytes; and the roles of such protein in the effects of toxicants

on immune functions.



o  Studies on aberrations in the elaboration and functions of

cytokines and cytokine receptors induced by toxicants.



o  Synergistic actions of physical/chemical agents either with each

other (e.g., a chemical and UV-B or two chemicals) or with other

agents such as viruses or oncogenes.



STUDY POPULATIONS



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 9, 1994 (FR 59 11146-11151) 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.



(NOTE:  When the proposed study or studies in the RFA or PA involves

a gender specific study or a single or limited number of minority

population groups, this should also be stated to inform potential

applicants and reviewers.)



Animal Welfare Considerations



Investigators are encouraged to consider alternative methods and

approaches in their research applications that do not require the use

of whole animals, use alternative species such as nonmammals or

invertebrates, reduce the number of animals required, and incorporate

refinements to procedures that will result in the elimination or

further minimization of pain and distress to animals.



APPLICATION PROCEDURES



Applications are to be submitted on form PHS 398 (rev. 9/91), which

is available in the office of sponsored research at most academic and

research institutions and from the Office of Grants Information,

Division of Research Grants, National Institutes of Health, Westwood

Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267.  To

identify the application as a response to this program announcement,

check "YES" in Item 2a on the face page of the application and enter

the program announcement title number.  Applications will be accepted

in accordance with the usual receipt dates for new research grant

applications; i.e., February 1, June 1, and October 1.  The earliest

possible award dates will be approximately nine months after the

respective receipt dates.  Applications received too late for one

cycle of review will be held until the next receipt date.



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.  Applications will be received

by the NIH Division of Research Grants (DRG) and referred to an

appropriate study section for scientific and technical merit review.

Institute assignment decisions will be governed by normal

programmatic considerations as specified in the NIH Referral

Guidelines.



The original and five copies of the application must be sent to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



The review criteria customarily employed by the NIH for regular

research grant applications will prevail.  Following the initial

scientific review, the applications will be evaluated by the

appropriate National Advisory Council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications assigned to that ICD.  The following will be considered

making funding decisions:



o  Quality of the proposed project as determined by peer review.

o  Availability of funds

o  Program balance among research areas of he announcement



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 to:



Dr. Eugene M. Zimmerman

Division of Allergy, Immunology and Transplantation

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4A24

Bethesda, MD  20892

Telephone:  (301) 496-8973

FAX:  (301) 402-2571



Dr. Jerry A. Robinson

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

P.O. Box 12233

Research Triangle Park, NC  27709

Telephone:  (919) 541-7724

FAX:  (919) 541-2843



To better ensure appropriate Program and Institute assignment,

applicants may submit a letter of intent and/or a copy of the

application face page to the Program Administrator, NIAID or NIEHS.



Direct inquiries regarding fiscal matters to:



David L. Mineo

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

P.O. Box 12233

Research Triangle Park, NC  27709

Telephone:  (919) 541-1373



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance Numbers 93.112, Characterization of Environmental Health

Hazards; 93.113, Biological Response to Environmental Health Hazards;

and 93.855, Allergy, Immunology and Transplantation Research.  Awards

are made under the authority of Section 487, Public Health Service

Act as amended (42 USC 288) and administered under PHS grants

policies and Title 42 of the Code of Federal Regulations, Part 66.

This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or Health Systems Agency

review.



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