ENVIRONMENTAL AGENTS AND ASTHMA

NIH GUIDE, Volume 23, Number 16, April 29, 1994



PA NUMBER:  PA-94-062



P.T. 34



Keywords:

  Asthma 

  Environmental Effects 



National Institute of Environmental Health Sciences

National Institute of Allergy and Infectious Diseases

National Heart, Lung, and Blood Institute



PURPOSE



The National Institute of Environmental Health Sciences (NIEHS), the

National Institute of Allergy and Infectious Diseases (NIAID), and

the National Heart, Lung, and Blood Institute (NHLBI) invite

applications to support research to determine the relationships

between exposure to environmental pollutants and allergens and the

induction and/or exacerbation of asthma in humans and to define the

mechanisms by which such environmental agents contribute to the

disease process of asthmatics.



The NIEHS is the principal Federal funding component to support

research scientifically examining the basic mechanisms by which

exposure to physical and chemical agents in the environment have

deleterious effects on human health and exacerbate human health

problems.  Many of these agents are airborne substances that

contribute to and/or exacerbate asthma and atopic diseases in

susceptible individuals.  The knowledge of mechanisms by which these

agents act will provide the sound scientific basis on which to

develop therapeutic and prophylactic measures for the treatment and

control of these environmentally-induced health problems.



The NIAID is the principal Federal funding component 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 diseases having a major

immunological component such as asthma and atopic diseases.



The NHLBI is the principal funding component that supports research

concerned with the structure and function of the pulmonary system in

health and disease.  The acquisition of new knowledge on the impact

of inhaled agents on the respiratory system and their role in the

pathogenesis and exacerbation of asthma is requisite to developing

methods for early diagnosis and prevention of disease as well as to

developing new methods for treatment.  The research mission of the

NHLBI extends to health education and outreach programs to examine

the environmental impact on lung complications from asthma.



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,

Environmental Factors and Asthma, is related to the priority areas of

environmental health and diabetes and chronic disabling diseases.

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 20402-0325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Research grant 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 of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible to apply for the First

Independent Research Support and Transition (FIRST) Award (R29).



MECHANISM OF SUPPORT



The mechanisms of support will be the individual research project

grant (R01) and the FIRST Award (R29).  Multidisciplinary approaches

that involve collaborative efforts among investigators in the fields

of basic and clinical immunology, allergy, pulmonology, biochemistry

and molecular biology are strongly encouraged.  Policies that govern

research grant programs of the National Institutes of Health will

prevail.



RESEARCH OBJECTIVES



Background



Asthma is a clinical condition, the symptoms of which include

intermittent shortness of breath and wheezing, chest tightness and

cough.  This condition is usually reversible either spontaneously or

as a result of treatment.  Asthma may be caused or provoked by

exposure to airborne pollutants encountered in the general

environment or the workplace.  Asthma is a common cause of morbidity

and disability, affecting an estimated two to five million children

and 20 million individuals in the USA.  Morbidity associated with

asthma accounts for an estimated 8.5 million physician and emergency

room visits annually; this translates into an estimated one million

work days lost that are related to asthma-associated disability.



A large number of agents in the environment and workplace have been

shown to induce asthma and asthma-like syndromes. Although the

proportion of asthma cases and asthma-like illness attributable to

environmental and occupational exposure is currently unknown,

evidence is accumulating that the inhalation of ozone, sulfuric acid,

and nitric acid, by individuals with allergic asthma, significantly

affects their respiratory capacity by decreasing lung volume and peak

flow.  The mechanisms responsible for pollutant-induced asthma are

uncertain and the appropriate pharmacologic interventions are

unknown.



A recent report by the Institute of Medicine, supported by the NIAID,

NIEHS, NHLBI and EPA, entitled "The Health Effects of Indoor

Allergens," highlighted the role of indoor allergens in asthma and

provided directions for research to explore this area.  The report

reviews recent data suggesting that indoor allergens, notably those

derived from dust mite, cat, and cockroach, are critical factors in

the etiology of asthma, and that individuals spend the vast majority

of their time in an indoor environment, presumably exposed to these

allergens.  Indeed, one important, but unproven, theory suggests that

asthma is increasing in prevalence because of changes in house

construction that have made homes "tight," resulting in increased

levels of indoor allergens as well as of other environmental agents

(e.g., irritants such as wood smoke and environmental tobacco smoke).

Outdoor pollutants are relevant as well, since such molecules as

ozone and oxides of nitrogen and sulfur are also present indoors.  It

is possible that irritants and pollutants act synergistically with

allergens.  The relative importance of these environmental agents are

unknown, but there are several examples of possible interactions

between irritants/pollutants and allergens for influencing both

airway hyperreactivity and immune responses.  Ozone and sulfur

dioxide, as mentioned above, are reported to worsen asthma and

increase bronchial hyperreactivity.  In animal models these

pollutants (and nitrogen oxides) are said to increase IgE antibody

production.  Diesel exhaust particulates apparently enhance IgE

antibody production to allergens.  Environmental tobacco exposure not

only reduces pulmonary function, but also appears to enhance IgE

antibody production to allergens.  The physicochemical nature of

particulates in the air also are said to regulate IgE antibody

production, perhaps because size, charge, and other properties

influence allergen binding and processing.  However, the mechanisms

by which these events occur have not been well characterized.  Thus,

this initiative represents a joint effort by NIEHS, NIAID, and NHLBI

to foster research programs to determine such relationships between

exposure to environmental pollutants and allergens and the induction

and/or exacerbation of asthma in humans.



Research Goals and Scope



Areas of research that would be responsive to this Program

Announcement should be focused on mechanistic studies, with both

basic and preclinical investigation, involving animal models,

cultured human cell models, and human patients.  These areas may

include, but are not limited to:



o  Evaluation of the role of pollutants (including environmental

tobacco smoke, diesel particulates, oxides of nitrogen and sulfur,

and others), in conjunction with allergen on both IgE antibody

production to allergen, and expression of clinical disease.



o  Examination of the effects of removal of pollutants and/or

allergen avoidance on reducing IgE antibody responses and preventing

clinical disease.



o  Defining the relationship between pollutant-mediated airway

hyperreactivity and allergen-mediated airway hyperreactivity.



o  Defining the relationship between outdoor allergens and other

environmental agents in the development and exacerbation of asthma.



o  Determining what differences between indoor and outdoor allergens

(and environmental factors such as pollutants) explain why indoor

allergen sensitivity correlates with asthma while outdoor allergen

sensitivity correlates with allergic rhinitis.



o  Determining the manner in which pollutants interact with viral

respiratory infections in the induction of asthma.



o  Determining the basic mechanisms by which pollutants alter the

inflammatory response in the airways, resulting in airways

hyperreactivity, IgE antibody production and asthma.  These studies

could concentrate on the response mechanism which may occur through

the modulation of neural function, epithelial cell function, antigen-

presenting cell function, inflammatory cell function, mediators,

cytokines, receptor modulation, and/or signalling pathways which may

be involved in the pathogenesis of asthma.



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 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 for the program

staff listed under INQUIRIES.  Program staff may also provide

additional relevant information concerning the policy.



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 301/594/-7248.  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 and 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.



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 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

in making funding decisions: quality of the proposed project as

determined by peer review;  availability of funds; program balance

among research areas of the 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:



George S. Malindzak, Jr., Ph.D.

Division of Extramural Research and Training

National Institute of Environmental Health Sciences

104 T.W. Alexander Drive

P.O. Box 12233

Research Triangle Park, NC  27709

Telephone:  (919) 541-3289

FAX:  (919) 541-2843



Marshall Plaut M.D.

Asthma and Allergy Branch

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4A23

Bethesda, MD  20892

Telephone:  (301) 496-8973

FAX:  (301) 402-2571



Suzanne S. Hurd, Ph.D.

Division of Lung Diseases

National Heart, Lung and Blood Institute

Westwood Building, Room 6416

Bethesda, MD  20892

Telephone:  (301) 594-7430

FAX:  (301) 594-7408



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



Jeffrey Carow

Immunology Grants Management Section

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B29

Bethesda, MD  20892

Telephone:  (301) 496-7075



Mr. Raymond L. Zimmerman

Division of Extramural Affairs

National Heart, Lung and Blood Institute

Westwood Building, Room 4A11C

Bethesda, MD  20892

Telephone:  (301) 594-7430



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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