Ion channels as mechanic modulators of epithelial tissue homeostasis

项目摘要 机械转导描述了将机械刺激转化为 生物化学信号，从而使细胞能够适应动态的物理环境。 机械感觉通路对发育和动态平衡是必不可少的，并受到损害 机械转导与多种疾病有关。然而，目前还不清楚哪些细胞 是机械敏感的吗，机械传感是如何调节的，以及什么机制与机械联系在一起 强制传递细胞内信号。探讨机械敏感离子通道复合体在细胞内的作用 胚胎发育将为这些重要问题提供关键见解。在这项提议中，我的目标是 为了了解钙激活的氯离子通道Ano1/TMEM16A和Piezo1是如何 机械敏感通道，可以将机械信号转化为细胞内生化信号。 我的初步分析表明，在小鼠胚胎发育过程中，Ano1的失活导致 胸骨缺损、心血管畸形、气管软化和食道狭窄，以及 肾发育不良，所有这些都与在Vacterl联合中观察到的影响 人类的多个器官。这些数据表明，在ano1突变体中发现的细胞缺陷可能会出现。 从机械感觉受损的角度，提出了一种Ano1和Piezo1协同作用的模型 控制形态发生的机械转导途径。我假设Ano1的行为 可能通过Piezo1介导的钙增加来调节，进而调节细胞内 调节细胞体积、数量、几何形状和增殖的机械。在具体目标1中，我将 研究Ano1和Piezo1在胚胎发育过程中的作用。在具体目标2中，我将确定 Ano1和Piezo1在调节机械敏感电流中的功能和生理偶联。 在特定的目标3中，我将使用体内和体外模型来研究可能的联系机制 Ano1和Piezo1在胚胎发育和动态平衡过程中的机械传感。结果将会是 首次表明Ano1介导的CACC与Piezo1协同作用以控制 形态发生，这一发现对于我们理解机械力如何与 哺乳动物发育中的通道功能和钙信号转导。我期待着我的提议 这项研究将为机械传感相关疾病的最终治疗策略开辟道路， 包括先天性出生缺陷和多囊肾疾病。

Project Summary Mechanotransduction describes the cellular processes that translate mechanical stimuli into biochemical signals, thus enabling cells to adapt to their dynamic physical surroundings. Mechanosensing pathway is essential to development and homeostasis, and impaired mechanotransduction is implicated in a wide spectrum of diseases. However it is unclear which cells are mechanosensitive, how mechanosensing is regulated and what mechanisms link mechanical forces to intracellular signaling. Examining the role of mechanosensitive ion channel complex in embryonic development will provide key insights into those important questions. In this proposal, I aim to understand how Ano1/Tmem16A, a calcium-activated chloride channel, and Piezo1, a machanosensitive channel, can transduce mechanical cues into intracellular biochemical signaling. My preliminary analyses show that inactivation of Ano1 during mouse embryonic development leads to sternum defect, cardiovascular anomalies, tracheomalacia and esophagus stenosis, as well as renal dysplasia, all of which resemble the phenotypes observed in VACTERL association that affect multiple organs in humans. The data indicate that cellular defects seen in Ano1 mutants may arise from impaired mechanosensing and suggest a model in which Ano1 and Piezo1 act synergistically in the mechanotransduction pathway to control morphogenesis. I hypothesize that the action of Ano1 may be modulated through Piezo1-mediated calcium increase, and in turn regulates intracellular machinery to adjust cell volume, number, geometry and proliferation. In Specific Aim 1, I will characterize the roles of Ano1 and Piezo1 during embryogenesis. In Specific Aim 2, I will determine the functional and physiological coupling of Ano1 and Piezo1 in regulating mechanosensitive current. In Specific Aim 3, I will use in vivo and in vitro models to investigate possible mechanisms that link Ano1 and Piezo1 in mechanosensing during embryogenesis and homeostasis. The results will provide the first indication that Ano1-mediated CaCC acts in concert with Piezo1 to control morphogenesis, a finding that is crucial for our understanding of how mechanical force integrates with channel function and calcium signaling in mammalian development. I anticipate that my proposed study will open the way to eventual treatment strategies for mechanosensing associated diseases, including congenital birth defects and polycystic kidney disorders.