EAGER: Exploratory role of microRNA-induced dysregulation of FOXO and Sirt1 in aging muscles

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PI: Boriek, Aladin M.Proposal Number: 1451619The proposed studies explore the effects of mechanical stretch on intracellular signaling pathways that protect from oxidative stress and address how these pathways are affected by aging. Data generated in the course of the proposed project have the potential to uncover, for the first time, the involvement of specific intracellular regulatory molecules in the function of anti-oxidative pathways in the aging respiratory pump. The proposed studies are expected to provide novel insights into understanding the functional impairment of respiratory muscles and potentially guide interventional strategies for slowing aging. The overall goal of this early stage developmental research project is to investigate how mechanotransduction is disrupted in aging muscles of the ventilatory pump and whether microRNAs play an important regulatory role in this process. The following specific aims are proposed. 1. To explore mechanisms responsible for loss of mechanosensitivity of signaling pathways regulating Sirt1 in old skeletal muscles of the diaphragms. 2. To explore possible dysregulation of specific mechanosensitive Sirt1 targets in the aging muscles of the ventilatory pump. 3. To explore a potential role of a particular microRNA, miR-200c, in the regulation of FOXO and Sirt1 in aging muscles of the ventilatory pump. Results from this developmental research project could provide for the first time new fundamental information on the novel signaling role of specific microRNAs in the regulation of the anti-aging gene, Sirt1. In addition, the proposed studies are likely to uncover new mechanisms that are responsible for the dysregulation of mechanosensing signaling pathways, and could spur further signal mechanotransduction work on the aging cardiac and smooth muscles. Hence, the proposed studies may generate information that could potentially contribute to guide interventional approaches for slowing aging. The investigators will attract undergraduates through Baylor College of Medicine SMART Program that supports under-represented students to pursue research careers initially as undergraduates. The investigators will continue to work with the graduate students in molecular physiology at Baylor College of Medicine. The proposed project will provide a working model of a successful integration of education and research training for strengthening the ongoing multidisciplinary collaboration between molecular physiology and cell biology at Baylor College of Medicine. Additionally, the PI plans the development of a new graduate course, and to continue his outreach activities with the Iman Academy High School students in the Houston area and with the Michael DeBakey Museum at Baylor College of Medicine.