Inner retinal dysfunction in retinitis pigmentosa

项目摘要 视网膜色素变性(RP)是遗传性视网膜疾病(IRD)中最常见的一组，导致 进行性光感受器退化和失明。除了经过充分研究的视网膜外层功能障碍外， RP，有越来越多的严谨工作强调视网膜内部的细胞适应，可能是由于 去传入后的神经重塑。这种结构重塑对血管内膜功能的影响 视网膜及其对视觉功能的影响目前还知之甚少。视网膜电图(ERG) 提供了一种在临床和动物模型中评估视网膜内部功能障碍的非侵入性方法 视网膜色素变性，不仅提供了对这些问题的见解，还提供了一种翻译 对患者潜在治疗策略的机械性见解。候选人的长期目标是 成为一名独立的临床医生-科学家，拥有必要的技能来实施预防或恢复 红斑狼疮患者的视力丧失。当前提议的科学目标是检验新的假设， 在视网膜患者和动物模型中使用新的ERG方案的初步数据支持 变性，即视网膜重塑导致视网膜内神经元的异常反应(噪声) 对视觉刺激的反应。该提案的首要目标是为候选人提供 导师、技能和支持，以实现致力于改善退化中的信号传输的职业生涯 视网膜。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性 改善光感受器功能的所有疗法的改进。在目标1中，视网膜内的范围 将使用新的ERG技术评估患有RP的人类受试者的功能障碍。AIM 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；目标3将 在视网膜神经节细胞的细胞内记录中明确光感受器变性的功能影响 RD10小鼠。这份提案描述了一项为期4年的培训计划，旨在发展学术生涯，重点是 在一支出色的多学科导师团队下了解IRD患者的视网膜功能障碍 候选人的科学独立目标。该提案将充分利用候选人的研究成果 在导师的指导下进行神经科学培训和临床团契培训IRDS和玻璃体视网膜手术 在临床视网膜电生理学和心理物理学方面有丰富经验的团队(杰森博士 动物电生理学和遗传学(Neal Peaceh博士)，以及单细胞电生理学和 成像(史蒂夫·德弗里斯博士)。课程和研讨会将补充导师团队在实现 伦理学基础研究和翻译研究。眼科和眼科的制度环境 伊利诺伊大学芝加哥分校的视觉科学，拥有一批杰出的视觉科学家和 卓越的设施，将最大限度地提高应聘者在研究和职业发展方面的成功。

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.