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.

该提案描述了一个为期 5 年的培训计划，旨在发展学术生涯，重点研究 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治疗的新策略 通过了解眼睛的机械感觉机制来治疗青光眼。虽然眼压 (IOP) 是青光眼最重要的危险因素，机械敏感蛋白的识别和功能 眼睛仍然很大程度上未知。我将使用人类遗传分析、体外分子和电生理学分析 方法和青光眼体内小鼠模型来研究机械敏感离子通道在 介导青光眼中视网膜神经节细胞（RGC）死亡。初步结果已鉴定出人类变异 与青光眼风险相关的机械敏感离子通道基因。我假设机械敏感离子 视网膜细胞中的通道感知 IOP 并介导青光眼中的 RGC 死亡，而人类变异赋予 这些职能的风险存在差异。目标 1 确定机械敏感离子通道对 体外机械刺激下视网膜细胞中的压力激活电流。目标 2 研究人类如何 机械敏感离子通道基因的变体改变异源系统中的通道功能。目标 3 测试 机械敏感通道在青光眼小鼠模型中的作用。拟议的研究有可能 深入了解 IOP 如何导致 RGC 死亡，并确定青光眼的新治疗靶点。与我的 感觉神经科学和电生理学的研究生培训，使我有能力进行这项研究。 我的职业发展计划将使我能够 1) 学习视网膜生理学，2) 发展知识和技术 机械感觉领域的专业知识，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资助能力、领导能力和管理技能。我受到支持 由一群忠诚的导师组成，他们致力于推进我作为独立临床科学家的职业生涯。 我将与视网膜生理学专家 Stephen Baccus 博士、转化性青光眼研究的领导者 Dr. Stephen Baccus 合作。 Jeffrey Goldberg、Yang Hu 博士和 Yang Sun 博士、机械感觉和离子通道专家 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。该培训将在斯坦福大学视觉和神经科学协作社区内进行 获得广泛的研究和职业发展资源。这项研究解决了一个关键需求 了解青光眼的机械感觉机制，并为我的职业生涯做好准备 NIH 资助的独立研究者，最终目标是将这些发现推进到临床 为这种常见的致盲疾病开发更好的治疗方法。