R01ES031940

Epidemiologic Identification and Mechanistic Investigation of Early Life Environmental Risk Factors for Eosinophilic Esophagitis

Abstract

Eosinophilic Esophagitis (EOE) is a recently recognized immune-mediated disease defined by abnormal infiltration of eosinophils into the esophageal mucosa. This condition leads to failure to thrive, abdominal pain, vomiting, and heartburn in children, and progresses to esophageal stenosis and food impaction in adults. Despite being initially thought to be rare, the incidence and prevalence of EOE are rising dramatically. Over the past decade, EOE has rapidly become a major cause of upper gastrointestinal morbidity. However, it is currently not possible to determine why individual patients develop EOE, which is frustrating for patients and practitioners alike.

EOE is considered to be an immune/allergen-mediated disease, and epidemiologic studies support a primarily environmental etiology. However, environmental risk factors have not been extensively studied in EOE. Prior studies, including those conducted by our own group, are limited by a crude assessment of exposures, recall bias, inability to assess fetal biomarkers, and lack of mechanistic understanding. Therefore, our goal is to address this knowledge gap by using an innovative method to precisely measure early life exposures in deciduous (primary, or "baby") teeth that may be implicated in EOE development.

Of particular interest are early life antibiotic exposure and the duration and intensity of breastfeeding, which can be derived from barium levels in teeth. Increased antibiotic exposure and decreased breastfeeding have been linked to the risk of atopic diseases. Measuring selected environmental exposures in teeth has never been applied to EOE, but we have documented the feasibility of this approach. This assessment, together with the use of novel cellular and molecular techniques for elucidating the mechanisms underlying the effects of these early life exposures, has the potential to greatly enhance our understanding of the pathogenesis of EOE.

Our hypothesis is that the risk of EOE related to early life exposures is primarily due to an impaired esophageal epithelial barrier, and that genetic susceptibility will interact with the exposures to modify risk. The specific aims of this study are to: 1) determine the association between early life antibiotic exposure and EOE; 2) determine whether breastfeeding is associated with EOE, and evaluate whether the susceptibility genotype for CAPN14 modifies the association between breastfeeding and EOE; and 3) determine the functional significance and mechanisms of early life exposures on esophageal epithelial architecture and barrier function.

To achieve these aims, we will conduct a case-control study to characterize temporal exposures, and in parallel, perform mechanistic analyses. This innovative, hypothesis-driven, and rigorously designed study will lead to robust and unbiased results. It will be conducted by a multidisciplinary team with recognized expertise in EOE, epidemiology, clinical/translational/lab research, and exposure science. The results will have a major impact on the understanding of EOE etiology and potentially identify opportunities for disease prevention, which could lead to the development of new treatment options.

University Of North Carolina At Chapel Hill

TO FOSTER UNDERSTANDING OF HUMAN HEALTH EFFECTS OF EXPOSURE TO ENVIRONMENTAL AGENTS IN THE HOPE THAT THESE STUDIES WILL LEAD TO: THE IDENTIFICATION OF AGENTS THAT POSE A HAZARD AND THREAT OF DISEASE, DISORDERS AND DEFECTS IN HUMANS, THE DEVELOPMENT OF EFFECTIVE PUBLIC HEALTH OR DISEASE PREVENTION STRATEGIES, THE OVERALL IMPROVEMENT OF HUMAN HEALTH EFFECTS DUE TO ENVIRONMENTAL AGENTS, THE DEVELOPMENT OF PRODUCTS AND TECHNOLOGIES DESIGNED TO BETTER STUDY OR AMELIORATE THE EFFECTS OF ENVIRONMENTAL AGENTS, AND THE SUCCESSFUL TRAINING OF RESEARCH SCIENTISTS IN ALL AREAS OF ENVIRONMENTAL HEALTH RESEARCH. SUPPORTED GRANT PROGRAMS FOCUS ON THE FOLLOWING AREAS: (1) UNDERSTANDING BIOLOGICAL RESPONSES TO ENVIRONMENTAL AGENTS BY DETERMINING HOW CHEMICAL AND PHYSICAL AGENTS CAUSE PATHOLOGICAL CHANGES IN MOLECULES, CELLS, TISSUES, AND ORGANS, AND BECOME MANIFESTED AS RESPIRATORY DISEASE, NEUROLOGICAL, BEHAVIORAL AND DEVELOPMENTAL ABNORMALITIES, CANCER, AND OTHER DISORDERS, (2) DETERMINING THE MECHANISMS OF TOXICITY OF UBIQUITOUS AGENTS LIKE METALS, NATURAL AND SYNTHETIC CHEMICALS, PESTICIDES, AND MATERIALS SUCH AS NANOPARTICLES, AND NATURAL TOXIC SUBSTANCES, AND THEIR EFFECTS OF ON VARIOUS HUMAN ORGAN SYSTEMS, ON METABOLISM, ON THE ENDOCRINE AND IMMUNE SYSTEMS, AND ON OTHER BIOLOGICAL FUNCTIONS, (3) DEVELOPING AND INTEGRATING SCIENTIFIC KNOWLEDGE ABOUT POTENTIALLY TOXIC AND HAZARDOUS CHEMICALS BY CONCENTRATING ON TOXICOLOGICAL RESEARCH, TESTING, TEST DEVELOPMENT, VALIDATION AND RISK ESTIMATION, (4) IDENTIFYING INTERACTIONS BETWEEN ENVIRONMENTAL STRESSORS AND GENETIC SUSCEPTIBILITY AND UNDERSTANDING BIOLOGIC MECHANISMS UNDERLYING THESE INTERACTIONS, INCLUDING THE STUDY OF ENVIRONMENTAL INFLUENCES ON EPIGENOMICS AND TRANSCRIPTIONAL REGULATION, (5) CONDUCTING ENVIRONMENTAL PUBLIC HEALTH RESEARCH, INCLUDING IN AREAS OF ENVIRONMENTAL JUSTICE AND HEALTH DISPARITIES, THAT REQUIRES COMMUNITIES AS ACTIVE PARTICIPANTS IN ALL STAGES OF RESEARCH, DISSEMINATION, AND EVALUATION TO ADVANCE BOTH THE SCIENCE AND THE DEVELOPMENT OF PRACTICAL MATERIALS FOR USE IN COMMUNITIES, WITH A FOCUS ON TRANSLATING RESEARCH FINDINGS INTO TOOLS, MATERIALS, AND RESOURCES THAT CAN BE USED TO PREVENT, REDUCE, OR ELIMINATE ADVERSE HEALTH OUTCOMES CAUSED BY ENVIRONMENTAL EXPOSURES, (6) EXPANDING AND IMPROVING THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) EXPANDING AND IMPROVING THE STTR PROGRAM TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (8) PROVIDING SUPPORT FOR BROADLY BASED MULTI-DISCIPLINARY RESEARCH AND TRAINING PROGRAMS IN ENVIRONMENTAL HEALTH .THESE PROGRAMS INCLUDE THE ENVIRONMENTAL HEALTH SCIENCES CORE CENTERS , WHICH SERVE AS NATIONAL FOCAL POINTS AND RESOURCES FOR RESEARCH AND MANPOWER DEVELOPMENT. THROUGH THESE PROGRAMS, NIEHS EXPECTS TO ACHIEVE THE LONG-RANGE GOAL OF DEVELOPING NEW CLINICAL AND PUBLIC HEALTH APPLICATIONS TO IMPROVE DISEASE PREVENTION, DIAGNOSIS, AND THERAPY. ADDITIONAL CENTERS PROGRAMS DEVELOPED IN RECENT YEARS, INCLUDE THE CENTERS FOR OCEANS AND HUMAN HEALTH (CO-FUNDED WITH NSF), CHILDREN'S ENVIRONMENTAL HEALTH CENTERS (CO-FUNDED WITH US EPA) AND THE AUTISM CENTERS OF EXCELLENCE (CO-FUNDED WITH OTHER NIH INSTITUTES), AND THE HUMAN HEALTH EXPOSURE ANALYSIS RESOURCE (HHEAR) PROGRAM, (9) SUPPORTING RESEARCH TRAINING PROGRAMS WHICH SERVE TO INCREASE THE POOL OF TRAINED RESEARCH MANPOWER WITH NEEDED EXPERTISE IN THE ENVIRONMENTAL HEALTH SCIENCES THROUGH SUPPORT OF INDIVIDUAL AND INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS), (10) THE OUTSTANDING NEW ENVIRONMENTAL SCIENTIST PROGRAM WHICH PROVIDES FIRST TIME RESEARCH GRANT FUNDING TO OUTSTANDING JUNIOR SCIENTISTS IN THE FORMATIVE STAGES OF THEIR CAREER WHO ARE PROPOSING TO MAKE A LONG TERM COMMITMENT TO ENVIRONMENTAL HEALTH SCIENCES RESEARCH AND TO ADDRESS THE ADVERSE EFFECTS ON ENVIRONMENTAL EXPOSURES ON HUMAN BIOLOGY, HUMAN PATHOPHYSIOLOGY AND HUMAN DISEASE.

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 01/31/26 to 01/31/27 and the total obligations have increased 362% from $696,693 to $3,217,424.