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

PI: Boriek, Aladin m .提案号：1451619提议的研究探讨机械拉伸对细胞内信号通路的影响，保护氧化应激，并解决这些途径如何受到衰老的影响。在拟议的项目过程中产生的数据有可能首次揭示特定的细胞内调节分子参与衰老呼吸泵抗氧化途径的功能。这些研究有望为理解呼吸肌功能损伤提供新的见解，并有可能指导延缓衰老的干预策略。这个早期发育研究项目的总体目标是研究机械转导在呼吸泵老化肌肉中是如何被破坏的，以及microrna是否在这一过程中发挥重要的调节作用。提出以下具体目标。1. 探讨老龄膈肌骨骼肌Sirt1信号通路机械敏感性丧失的机制。2. 探讨通气泵老化肌肉中特定机械敏感Sirt1靶点可能的失调。3. 探索特定的microRNA miR-200c在调节呼吸泵老化肌肉中FOXO和Sirt1中的潜在作用。这一发展性研究项目的结果可能首次为特异性microrna在抗衰老基因Sirt1调控中的新信号作用提供新的基础信息。此外，提出的研究可能会揭示机械传感信号通路失调的新机制，并可能进一步刺激衰老的心脏和平滑肌的信号机械转导工作。因此，提出的研究可能会产生可能有助于指导延缓衰老的干预方法的信息。研究人员将通过贝勒医学院SMART项目吸引本科生，该项目支持代表性不足的学生最初作为本科生从事研究工作。研究人员将继续与贝勒医学院分子生理学专业的研究生合作。拟议的项目将提供一个成功整合教育和研究培训的工作模式，以加强贝勒医学院分子生理学和细胞生物学之间正在进行的多学科合作。此外，PI计划开发一门新的研究生课程，并继续与休斯顿地区的伊曼学院高中学生和贝勒医学院的迈克尔·德贝基博物馆开展外展活动。

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.