Monday, May 19, 2025
5/19/2025
MicroRNAs in Airway Smooth Muscle Function and Asthma - MicroRNAs in Airway Smooth Muscle Function and Asthma PROJECT SUMMARY Over 300 million people, many of them children, suffer from asthma. Airway smooth muscle (ASM) controls airway narrowing and plays a pivotal role in the pathogenesis of asthma. Asthmatic ASM becomes hyper-proliferative, increases in size, and may be more contractile. These phenotypic changes in ASM contribute directly to airway remodeling and airway hyperresponsiveness (AHR)—cardinal features of asthma. Targeting ASM thus could provide direct and effective ways to treat asthma but requires deeper understanding of the underlying molecular mechanisms that regulate the various ASM phenotypes. MicroRNAs are small yet powerful gene tuners that have the potential to impact diverse cellular processes such as the ASM phenotypes. My lab has performed multiple functional, phenotype-based screens, using both microRNA mimics (for overexpression) and focused CRISPR knockout libraries, on the top 100 ASM microRNAs to identify those that directly regulate critical ASM phenotypes, including proliferation, hypertrophy and contractility. The overarching goal of this proposal is to establish the in vivo role of top microRNA hits in regulating the corresponding ASM function and AHR, and to demonstrate that perturbation of such regulation contributes to human asthma and alters response to asthma therapies. To achieve this goal, we propose multi-disciplinary and integrative research that combines mechanistic studies in primary ASM cells, in vivo mouse models, and genetic epidemiology in human asthma populations. Aim 1 will test the targeting of microRNA-34a and microRNA-432 to reduce ASM mass and AHR. Aim 2 will test the targeting of microRNA-486 to reduce ASM contractility and AHR. Aim 3 will determine the functional association of microRNA-34a/432/486 and their target genes with asthma and with responses to asthma therapy. Results from this study will establish microRNAs as master regulators of multiple critical ASM phenotypes and provide pre-clinical evidence for further developing microRNAs-based therapeutics for asthma patients.
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