Ion channels as mechanic modulators of epithelial tissue homeostasis

离子通道作为上皮组织稳态的机械调节剂

• 批准号: 9453574
• 负责人: Mu He
• 金额: $ 6.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453574
• 关键词: Actomyosin; Affect; Architecture; Biochemical; Biomechanics; Blood Vessels; Cadherins; Calcium; Calcium Signaling; Cardiovascular system; Cell Cycle; Cell Volumes; Cell physiology; Cells; Chloride Channels; Cilia; Complex; Congenital Abnormality; Coupling; Cues; Cultured Cells; Data; Defect; Development; Disease; Dysplasia; Electrophysiology (science); Embryo; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Esophagus; Exhibits; Gene Expression; Geometry; Global Change; Homeostasis; Human; Image; Impairment; In Vitro; Individual; Ion Channel; Kidney; Kidney Diseases; Lead; Light; Link; Lung; Malignant Neoplasms; Mammary gland; Mechanics; Mediating; Modeling; Morphogenesis; Morphology; Mus; Muscle Contraction; Organ; Pathologic; Pathway interactions; Pattern; Pattern Formation; Perinatal mortality demographics; Pharmacology; Phenotype; Physiological; Physiological Processes; Play; Polycystic Kidney Diseases; Process; Pseudostratified Epithelium; Renal tubule structure; Respiratory System; Role; Sensory; Shapes; Signal Pathway; Signal Transduction; Simple Cuboidal Epithelium; Smooth Muscle; Stenosis; Sternum; Stimulus; Stress; Testing; Tissues; Tracheal Epithelium; Translating; VATER (vertebral defects-anal atresia-tracheoesophageal fistula-esophageal atresia-radial and renal dysplasia) association or syndrome; biological systems; bone; cardiogenesis; cell growth; channel blockers; chemical genetics; ciliopathy; cilium biogenesis; in vitro Model; in vivo; insight; kidney epithelial cell; knock-down; malformation; matrigel; mechanical force; mechanotransduction; mutant; nephrogenesis; novel; patch clamp; protein complex; treatment strategy

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.

项目摘要 机械转导描述了将机械刺激转化为细胞信号的细胞过程。 生物化学信号，从而使细胞能够适应其动态的物理环境。 机械感应通路对于发育和稳态是必不可少的， 机械传导与广泛的疾病有关。但目前还不清楚哪些细胞 是机械敏感的，机械感知是如何调节的，以及什么机制将机械 对细胞内信号传导的影响检查机械敏感性离子通道复合物在 胚胎发育将为这些重要问题提供关键的见解。在这份提案中，我的目标是 为了了解钙激活氯离子通道Ano 1/Tmem 16 A和钙激活氯离子通道Piezo 1是如何相互作用的， 机械敏感通道，可以将机械信号转换为细胞内的生化信号。 我的初步分析表明，在小鼠胚胎发育过程中，Ano 1的失活导致 胸骨缺损、心血管异常、气管软化和食管狭窄，以及 肾发育不良，所有这些都类似于在VEGIL相关中观察到的表型， 人体的多个器官。这些数据表明，在Ano 1突变体中观察到的细胞缺陷可能会出现 从受损的机械感知，并提出了一个模型，其中Ano 1和Piezo 1协同作用， 控制形态发生的机械传导途径。我假设Ano 1的作用 可能通过Piezo 1介导的钙离子增加来调节，进而调节细胞内 机械调节细胞体积、数量、几何形状和增殖。在具体目标1中，我将 描述Ano 1和Piezo 1在胚胎发生过程中的作用。在第二个目标中，我将决定 Ano 1和Piezo 1在调节机械敏感电流中的功能和生理耦合。 在具体目标3中，我将使用体内和体外模型来研究可能的机制， Ano 1和Piezo 1在胚胎发育和稳态过程中的机械传感。结果将 提供了Ano 1介导的CaCC与Piezo 1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 通道功能和钙信号在哺乳动物的发展。我预计我的提议 这项研究将为机械感应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。