Miz1: Mechanistic Insights into Endotoxin-Induced Protection Against Allergenic Asthma and Its Therapeutic Potential

Project Summary/Abstract Asthma is a prevalent chronic disease with no current cure, despite recent improvements in diagnosis and management. The "hygiene hypothesis" suggests that early exposure to microbes protects against asthma, which has gained support from increasing evidence, but the underlying mechanisms remain unclear. Our long- term goal is to uncover the molecular mechanisms responsible for the protective effects of early endotoxin exposure against asthma. The objective of this proposal is to examine the role for Miz1 in asthma with relation to the “hygiene hypothesis”. Our central hypothesis is that endotoxin-induced downregulation of Miz1 provides protection against allergic asthma through epigenetic regulation. Our rationale is that identification of the mechanisms to target the Miz1 pathway may offer new therapeutic approaches to prevent and treat asthma. The central hypothesis will be tested by pursuing three specific aims: Specific Aim 1 will investigate the molecular mechanisms of Miz1 downregulation by endotoxin and its role in mediating the protective effect of endotoxin against allergic asthma; Specific Aim 2 will determine the underlying molecular mechanisms by which endotoxin-induced Miz1 downregulation confers protection against allergic asthma; Specific Aim 3 evaluate the therapeutic efficacy of Miz1 pathway targeting in an experimental asthma model and determine whether components of the Miz1 pathway are deregulated in allergen-challenged human asthmatic. This study is significant, as identification of new targets of the Miz1 pathway may lead to the development of novel therapeutics for asthma, a debilitating condition with no targeted or efficient treatment. The proposed research is conceptually innovative because Miz1-mediated epigenetic regulation may provide a long-sought “missing link” for the association between earlier endotoxin exposure and decreased asthma prevalence. We also utilize innovative approaches, which combine cutting-edge analytical and manipulative methods in both cellular, animal, and human studies. These investigations are impactful as they may provide potential mechanisms for the “hygiene hypothesis” and fundamental insights into the pathogenesis of asthma, leading to new therapeutic targets.