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.

该建议描述了一项为期5年的培训计划，旨在开发专注于研究的学术职业 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 通过了解眼睛中的机械效率的机制，青光眼。虽然眼内压 （IOP）是青光眼最重要的危险因素，是机械敏感蛋白在中的识别和功能 眼睛在很大程度上仍然未知。我将使用人类遗传分析，体外分子和电生理学 方法和青光眼的体内小鼠模型研究机械敏感离子通道在 介导视网膜神经节细胞（RGC）在青光眼中死亡。初步结果已经确定了人类的变体 机械敏感的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IOP并介导青光眼中的RGC死亡，并且人类变体赋予 这些功能的差异风险。 AIM 1确定机械敏感离子通道对 机械刺激后，视网膜细胞中的压力激活电流。 AIM 2调查了人类 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 机械敏感通道在青光眼小鼠模型中的作用。拟议的研究有可能 提供有关IOP如何导致RGC死亡并确定青光眼的新型治疗靶标的见解。和我的 在感觉神经科学和电生理学方面的研究生培训，我有能力进行这项研究。 我的职业发展计划将允许我到1）学习视网膜生理学，2）发展知识和技术 机械敏化领域的专业知识，3）获得青光眼小鼠模型的经验，4） 发展赠款，领导和管理技能，以领导独立的研究团队。我得到了支持 由一个致力于促进我作为独立临床医生职业的导师团队的团队。 我将与视网膜生理专家Stephen Baccus博士，转化青光眼研究的领导者Stephen Baccus博士。 杰弗里·戈德堡（Jeffrey Goldberg），杨胡（Yang Hu）博士和杨太阳博士（Dr. Yang Sun），机械敏感和离子频道专家阿德姆博士 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 wiggs。这项培训将在斯坦福的协作愿景和神经科学社区中进行，与 访问其广泛的研究和职业发展资源。这项研究解决了一个迫切的需求 了解青光眼中的机械效率机理，并为我做好准备 独立NIH资助的研究人员，最终的目的是将这些发现推向床边 为这种常见的盲目疾病开发更好的治疗方法。