Inner retinal dysfunction in retinitis pigmentosa

色素性视网膜炎的内部视网膜功能障碍

• 批准号: 10507649
• 负责人: Robert Hyde
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507649
• 关键词: Amacrine Cells; Animal Model; Animals; Area; Attenuated; Basic Science; Biological Markers; Blindness; Cells; Characteristics; Chicago; Clinic; Clinical; Clinical Investigator Award; Complement; Coupling; Data; Deafferentation procedure; Degenerative Disorder; Development; Doctor of Philosophy; Electrophysiology (science); Electroretinography; Environment; Ethics; Exhibits; Fellowship; Frequencies; Functional disorder; Future; Genetic; Goals; Illinois; Image; Inherited; Lead; Masks; Measures; Mediating; Mentors; Mentorship; Methods; Mus; Nature; Neurosciences; Noise; Operative Surgical Procedures; Ophthalmology; Patients; Periodicity; Pharmacology; Photoreceptors; Protocols documentation; Psychophysics; Research; Research Personnel; Research Training; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Scientist; Signal Transduction; Source; Standard Model; Stimulus; Structure of retinal pigment epithelium; Synaptic Potentials; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Training Programs; Translating; Translational Research; Universities; Vision; Work; career; career development; cell type; clinical practice; design; effective therapy; experience; functional improvement; ganglion cell; human subject; improved; indexing; insight; mouse model; multidisciplinary; novel; photoreceptor degeneration; prevent; relating to nervous system; repaired; research and development; response; retinal damage; retinal neuron; sight restoration; skills; success; therapeutic target; translational research program; transmission process; trial design; vision science; visual dysfunction; visual stimulus

Project Abstract Retinitis pigmentosa (RP) is the most common group of inherited retinal diseases (IRDs), leading to progressive photoreceptor degeneration and blindness. In addition to well-studied outer retinal dysfunction in RP, there is a growing body of rigorous work highlighting cellular adaptations in the inner retina, likely due to neural remodeling following deafferentation. The impact of this structural remodeling on the function of inner retina, and its consequences for visual function, are at present poorly understood. Electroretinography (ERG) provides a non-invasive method to assess inner retinal dysfunction both in the clinic and in animal models of retinitis pigmentosa, providing a means not only to provide insights into these questions, but also to translate mechanistic insights into potential therapeutic strategies for patients. The long term goal of the candidate is to become an independent clinician-scientist with the skills necessary to pursue strategies to prevent or restore vision loss in patients with IRDs. The scientific objective of the current proposal is to test the novel hypothesis, supported by preliminary data using a novel ERG protocol in both patients and animal models of retinal degeneration, that retinal remodeling leads to aberrant responses (noise) in inner retinal neurons that mask responses to a visual stimulus. The overarching goal of the proposal is to provide the candidate with the mentorship, skills, and support to realize a career dedicated to improve signal transmission in the degenerating retina. This is an essential area of research, as aberrant inner retinal responses limit the potential for functional improvement in all therapies that improve photoreceptor function. In Aim 1, the extent of inner-retina dysfunction will be assessed using novel ERG techniques in human subjects with RP. Aim 2 will develop ERG approaches to assess inner retinal remodeling in a mouse model of RP (the rd10 mouse model); Aim 3 will define the functional impact of photoreceptor degeneration in intracellular recordings of retinal ganglion cells in rd10 mice. This proposal describes a 4-year training program for developing an academic career focused on understanding retinal dysfunction in IRDs under an outstanding team of multidisciplinary mentors dedicated to the candidate’s objective of scientific independence. The proposal will leverage the candidate’s research training in neuroscience and clinical fellowship training in IRDs and vitreoretinal surgery under a mentorship team that has extensive experience in clinical retinal electrophysiology and psychophysics (Dr. Jason McAnany), animal electrophysiology and genetics (Dr. Neal Peachey), and single cell electrophysiology and imaging (Dr. Steve DeVries). Coursework and seminars will complement the mentorship team in the realization of ethical basic and translational research. The institutional environment in the Department of Ophthalmology & Visual Sciences at the University of Illinois-Chicago, with its corps of outstanding vision scientists and outstanding facilities, will maximize the candidate’s success in research and career development.

项目摘要 色素性视网膜炎（RP）是最常见的一组遗传性视网膜疾病（IRD），导致 除了经过充分研究的外视网膜功能障碍外，还会出现进行性感光细胞变性和失明。 RP，越来越多的严谨工作强调了视网膜内层的细胞适应，这可能是由于 传入神经阻滞后的神经重塑这种结构重塑对内部功能的影响。 目前，人们对视网膜及其对视觉功能的影响知之甚少。 提供了一种在临床和动物模型中评估内部视网膜功能障碍的非侵入性方法 视网膜色素变性，不仅提供了一种方法来深入了解这些问题，而且还提供了一种翻译方法 对患者潜在治疗策略的机制见解 候选人的长期目标是 成为一名独立的临床医生科学家，拥有采取预防或恢复策略所需的技能 IRD 患者的视力丧失当前提案的科学目标是检验新假设， 在视网膜患者和动物模型中使用新型 ERG 方案得到初步数据支持 退化，视网膜重塑导致视网膜内部神经元的异常反应（噪音），从而掩盖 该提案的总体目标是为候选人提供对视觉刺激的反应。 指导、技能和支持，以实现致力于改善退化环境中信号传输的职业生涯 这是一个重要的研究领域，因为异常的视网膜内部反应限制了功能的潜力。 改善所有改善感光器功能的疗法 在目标 1 中，视网膜内层的范围。 将使用新型 ERG 技术对患有 RP 的人类受试者进行功能障碍评估，目标 2 将开发 ERG。 评估 RP 小鼠模型（RD10 小鼠模型）内视网膜重塑的方法； 定义视网膜神经节细胞细胞内记录中光感受器变性的功能影响 rd10 小鼠。该提案描述了一个为期 4 年的培训计划，旨在发展学术生涯，重点关注 在杰出的多学科导师团队的指导下，了解 IRD 的视网膜功能障碍 候选人的科学独立性目标 该提案将利用候选人的研究。 神经科学和临床研究员培训 在导师指导下进行 IRD 和玻璃体视网膜手术培训 团队在临床视网膜电生理学和心理物理学方面拥有丰富的经验（Jason博士 McAnany）、动物电生理学和遗传学（Neal Peachey 博士）以及单细胞电生理学和 成像（史蒂夫·德弗里斯博士）课程作业和研讨会将补充指导团队的实现。 眼科的伦理基础和转化研究的制度环境。 伊利诺伊大学芝加哥分校视觉科学学院拥有一批杰出的视觉科学家和 一流的设施，将最大限度地提高候选人在研究和职业发展方面的成功。