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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