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）是最常见的遗传残留疾病（IRD），导致 进行性光感受器变性和失明。除了研究良好的外部视网膜功能障碍 RP，越来越严格的工作突出了内部视网膜中的细胞适应 死亡后的神经重塑。这种结构重塑对内部功能的影响 视网膜及其对视觉功能的后果目前的理解很差。遗传学（ERG） 提供了一种非侵入性方法，可以评估诊所和动物模型中的内部残留功能障碍 色素性视网膜炎，提供一种不仅提供对这些问题的见解，还提供翻译的手段 对患者潜在治疗策略的机械洞察力。候选人的长期目标是 成为独立的临床科学家，具有采取策略以防止或恢复所需的技能 IRD患者的视力丧失。当前建议的科学目标是检验新的假设， 在视网膜的患者和动物模型中使用新型ERG方案的初步数据支持 变性，重塑导致内部残留神经元中的异常反应（噪声） 对视觉刺激的反应。该提案的总体目标是为候选人提供 识别，技能和支持，以实现致力于改善退化信号传输的职业 视网膜。这是研究的重要领域，因为异常的内部残留响应限制了功能的潜力 改善了改善光感受器功能的所有疗法。在AIM 1中，内在的范围 功能障碍将使用RP人类受试者中的新型ERG技术进行评估。 AIM 2将发展ERG 在RP的小鼠模型（RD10小鼠模型）中评估内部仍重塑的方法；目标3意志 定义感光细胞变性在视网膜神经节细胞细胞内记录中的功能影响 RD10小鼠。该建议描述了一项为期4年的培训计划，用于发展专注于 在一个杰出的多学科导师团队的领导下 候选人的科学独立目标。该提案将利用候选人的研究 心态下的IRD和玻璃体视网膜手术的神经科学和临床奖学金培训培训 在临床视网膜电生理学和心理物理学方面拥有丰富经验的团队（Jason博士 Mcanany），动物电生理学和遗传学（Neal Peachey博士），单细胞电生理学和 成像（Steve Devries博士）。课程工作和精确将在实现中完成Mentalship团队 道德基础和翻译研究。眼科系的机构环境和 伊利诺伊州 - 芝加哥大学的视觉科学，其杰出视觉科学家和 出色的设施将最大化候选人在研究和职业发展方面的成功。