The primary objective of this research is to investigate the potential role of chronic environmental endotoxin exposure in asthma prevention in young children. Since asthma generally begins in early childhood, interventions and exposures that lessen the atopic immune development that underlies asthmatic inflammation may have their greatest efficacy in young children, prior to the advent of pathologic lung processes typical of the intractable disease state. Although endotoxin exposure has been shown, in adult asthmatics, to be pro-inflammatory and augment asthma, it is also well known to be a potent inducer of IFN-gamma or """"""""Type 1"""""""" immune responses, that are counter-regulatory to atopic """"""""Type 2"""""""" immune development. Therefore, the main hypothesis of this proposal is that chronic endotoxin exposure in young children will prevent asthma by enhancing Type 1 immunity, thereby inhibiting atopic immune development and airways inflammation. A recently funded NIH study, entitled the """"""""Childhood Asthma Prevention Study"""""""" (CAPS), provides an outstanding opportunity to explore this hypothesis in a supplemental manner. CAPS is a nurse home visitation intervention study that is enrolling 180 Inner-city infants with at least 3 previous episodes of wheezing, and following them until age 4 years for the development of asthma. Pilot studies supplemental to CAPS have demonstrated that, in these asthma-prone infants, increased house dust endotoxin levels are associated with less allergen sensitization and enhanced Type 1 immune responses. By continuing to study this CAPS study cohort, we propose to determine if chronic endotoxin exposure further reduces the prevalence of asthma at ages 6-7 years, by enhancing Type 1 immunity and thereby inhibiting allergen sensitization and Type 2 immune development. As well, several factors contributing to variations in immune responses to endotoxin will be studied. Ultimately, this research may serve to define the potential of augmenting Type 1 immunity in early life as a primary prevention strategy for asthma and allergy. New diagnostic tools to follow pro-asthmatic immune progression or resolution have been developed and will be tested in the process. This K23 Mentored Patient-Oriented Research Career Development Award will provide the Candidate, a Pediatric Asthma, Allergy & Immunology specialist, with the skills, experience, mentorship, and knowledge needed to be a productive and independent investigator in patient-oriented research. A specific Research Career Development Plan has been designed by the Candidate that includes the research described above in order to accomplish the goals of this Award.
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