The Role of Mechanosensitive Ion Channels in Glaucoma

机械敏感离子通道在青光眼中的作用

• 批准号: 10572841
• 负责人: Wendy W. Liu
• 金额: $ 24.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572841
• 关键词: Address; Affect; Astrocytes; Axon; Axonal Transport; Cell Death; Cell Line; Cell Survival; Cells; Communities; Data; Dedications; Development; Development Plans; Disease; Disease Progression; Electrophysiology (science); Exhibits; Eye; Foundations; Funding; Genes; Genetic; Glaucoma; Goals; Human; Human Genetics; Immunohistochemistry; In Situ Hybridization; In Vitro; Ion Channel; Knock-out; Knowledge; Lead; Leadership; Learning; Mammals; Mechanical Stimulation; Mechanical Stress; Mechanics; Mediating; Mentors; Mentorship; Modeling; Molecular; Mus; Neurosciences; Optic Disk; Pharmacology; Physiologic Intraocular Pressure; Physiological; Physiological Processes; Physiology; Piezo 1 ion channel; Piezo 2 ion channel; Piezo ion channels; Play; Property; Proteins; RNA; Research; Research Personnel; Resources; Retina; Retinal Ganglion Cells; Risk; Risk Factors; Role; Scientist; Silicone Oils; Stimulus; Stress; System; Technical Expertise; Testing; Tissues; Training; Training Programs; United States National Institutes of Health; Variant; Vision; Work; axonal degeneration; career; career development; cell type; common treatment; conditional knockout; experience; experimental study; genetic analysis; human data; in vivo; insight; modifiable risk; mouse model; neuroprotection; new therapeutic target; patch clamp; pressure; research and development; response; sensory neuroscience; skills; visual neuroscience

This proposal describes a 5-year training program to develop an academic career focused on investigating the role of mechanosensitive ion channels in glaucoma. My long-term goal is to discover new strategies for treating glaucoma by understanding the mechanisms of mechanosensation in the eye. Although intraocular pressure (IOP) is the most significant risk factor for glaucoma, the identify and function of mechanosensitive proteins in the eye remain largely unknown. I will use human genetic analyses, in vitro molecular and electrophysiological approaches, and in vivo mouse models of glaucoma to study the role of mechanosensitive ion channels in mediating retinal ganglion cell (RGC) death in glaucoma. Preliminary results have identified human variants in mechanosensitive ion channel genes associated with glaucoma risk. I hypothesize that mechanosensitive ion channels in retinal cells sense IOP and mediate RGC death in glaucoma, and that human variants confer differential risk in these functions. Aim 1 determines the contribution of mechanosensitive ion channels to pressure-activated currents in retinal cells in vitro upon mechanical stimulation. Aim 2 investigates how human variants of mechanosensitive ion channel genes alter channel function in a heterologous system. Aim 3 tests the role of mechanosensitive channels in a mouse model of glaucoma. The proposed studies have the potential to provide insight into how IOP leads to RGC death and identify novel therapeutic targets for glaucoma. With my graduate training in sensory neuroscience and electrophysiology, I am well equipped to conduct this research. My career development plan will allow me to 1) learn retinal physiology, 2) develop knowledge and technical expertise in the field of mechanosensation, 3) acquire experience with mouse models of glaucoma and 4) develop grantsmanship, leadership and managerial skills to lead an independent research team. I am supported by a committed team of mentors who are dedicated to advancing my career as an independent clinician scientist. I will work with retinal physiology expert Dr. Stephen Baccus, leaders in translational glaucoma research Dr. Jeffrey Goldberg, Dr. Yang Hu and Dr. Yang Sun, mechanosensation and ion channel experts Dr. Ardem Patapoutian, Dr. Miriam Goodman and Dr. Merritt Maduke, and human glaucoma genetics expert Dr. Janey Wiggs. This training will take place within the collaborative vision and neuroscience community at Stanford, with access to its extensive resources for research and career development. This research addresses a critical need to understand the mechanisms of mechanosensation in glaucoma and prepares me for a career as an independent NIH-funded investigator, with the ultimate goal of advancing these discoveries to the bedside to develop better treatments for this common blinding disease.

这份提案描述了一项为期5年的培训计划，旨在发展专注于研究 机械敏感离子通道在青光眼中的作用。我的长期目标是发现新的治疗方法 通过了解眼睛中的机械感觉机制来治疗青光眼。虽然眼压 眼压(IOP)是青光眼最重要的危险因素，机械敏感蛋白在青光眼中的识别和功能 眼睛在很大程度上仍不为人所知。我将使用人类基因分析，体外分子和电生理学 方法和在体小鼠青光眼模型中研究机械敏感离子通道在青光眼发病中的作用 介导青光眼视网膜神经节细胞(RGC)死亡。初步结果已经确定了人类变种在 机械敏感离子通道基因与青光眼风险相关。我假设机械敏感离子 视网膜细胞中的通道感觉眼压并介导青光眼中RGC的死亡，而人类变异提供了帮助 这些功能中的不同风险。目标1确定机械敏感离子通道对 机械刺激下视网膜细胞的压力激活电流。目标2调查人类是如何 机械敏感离子通道基因的变体改变了异源系统中的通道功能。AIM 3测试 机械敏感通道在小鼠青光眼模型中的作用。拟议的研究有可能 洞察眼压如何导致RGC死亡，并确定青光眼的新治疗靶点。带着我的 经过感觉神经科学和电生理学方面的研究生培训，我完全有能力进行这项研究。 我的职业发展计划将使我1)学习视网膜生理学，2)发展知识和技术 机械传感领域的专业知识，3)获得青光眼小鼠模型的经验；4) 培养领导独立研究团队的勇气、领导力和管理技能。我得到了支持 由致力于推动我作为一名独立临床医生科学家的职业生涯的导师组成的团队。 我将与视网膜生理学专家斯蒂芬·巴克斯博士合作，他是翻译性青光眼研究的领导者。 Jeffrey Goldberg、杨虎博士和孙杨博士，机械传感和离子通道专家Ardem博士 Patapoutian，Miriam Goodman博士和Merritt Maduke博士，以及人类青光眼遗传学专家Janey博士 威格斯。这项培训将在斯坦福大学的协作视野和神经科学社区内进行， 利用其广泛的资源进行研究和职业发展。这项研究解决了一个紧迫的需求 了解青光眼的机械感觉机制，为我的职业生涯做好准备 由美国国立卫生研究院资助的独立研究员，最终目标是将这些发现推进到床边 为这种常见的致盲疾病开发更好的治疗方法。