Cholinergic hyperinnernation in early life regulates long-term airway reactivity

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Project Summary: Asthma is a chronic respiratory disease affecting more than 25 million people including 7 million children in the United States and imposing a substantial health and economic burden on patients, their families and the communities. Although asthma may affect all age groups, it most often starts during childhood. Clinical observations have revealed early life environmental insults are associated with increased risk of chronic airway obstructive diseases including asthma. In addition, there is increasing recognition that lung function throughout life is profoundly impacted by respiratory events that occur during the time period of postnatal lung development. These findings highlight the significance of more fully understanding age-related specific airway adaptive changes from environmental exposures in early life. Our work in progress with an early life mouse asthma model has revealed a key role of neural dysregulation of airway smooth muscle (ASM) in the maintenance of airway hyperreactivity (AHR). We found early life allergen exposure induced a unique upregulation of ASM contractility via cholinergic hyperinnervation. This contractile plasticity of ASM in the time window of postnatal airway development played a key role in retaining long term AHR. In contrast, alteration in neural regulation and subsequent long term enhancement of airway contractility was not seen in a murine model of adult asthma. Moreover, microarray analysis of ASM revealed gene expression of CD38 and -actinin1 (ACTN1) was selectively upregulated in P21 ASM following allergen exposure. These genes have established role in the contractile regulation of ASM. We therefore hypothesize that cholinergic stimulation during postnatal development aberrantly activates Ca2+ and ACTN1- mediated pathways in ASM, which in turn causes persistent AHR. We propose to test this hypothesis by 1) identifying the critical time window during which ASM is vulnerable to the aberrant cholinergic regulation; 2) investigating two potential mechanisms underlying cholinergic stimulation induced ASM hypercontractility, ie CD38 mediated Ca2+ signaling pathway and ACTN1 mediated intracellular mechanotransduction; and 3) evaluating the efficacy of anti-cholinergic medication in the prevention of persistent AHR following early life allergen exposure. With the guidance of my mentors, Drs. Xingbin Ai and Bruce Levy, we have developed a five-year training program that includes both tailored didactic and technical training to develop additional skills for study of the regulation of ASM in health and disease. Importantly, this project will be overseen by a scientific career advisory committee with expertise related to key areas of this proposal, including ASM physiology, molecular and developmental lung biology and animal disease models. The proposed career development plan will establish scientific foundations and provide the additional training necessary to achieve my ultimate goal of becoming an independent, NIH-funded physician-scientist studying pulmonary smooth muscle biology and dysregulation in lung diseases.