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。除了研究充分的外视网膜功能障碍， RP，有越来越多的严格的工作强调细胞适应在视网膜内层，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分泌功能的影响 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） 提供了一种非侵入性的方法，以评估在临床和动物模型的视网膜功能障碍， 视网膜色素变性，提供了一种手段，不仅提供了这些问题的见解，但也翻译 对患者潜在治疗策略的机械见解。候选人的长期目标是 成为一名独立的临床科学家，掌握必要的技能，以寻求预防或恢复 IRD患者的视力下降。目前提案的科学目的是检验新的假设， 在视网膜病变患者和动物模型中使用新的ERG方案的初步数据支持了这一点。 变性，视网膜重塑导致内部视网膜神经元的异常反应（噪音）， 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，以实现一个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反应限制了功能性视网膜病变的可能性。 改善所有治疗，提高感光功能。在目标1中，内视网膜的范围 在患有RP的人类受试者中使用新的ERG技术来评估功能障碍。目标2将发展ERG 评估RP小鼠模型（rd 10小鼠模型）中视网膜重塑的方法; Aim 3将 定义视网膜神经节细胞的细胞内记录中光感受器变性的功能影响， rd 10小鼠。该提案描述了一个为期4年的培训计划，以发展学术生涯，重点是 在多学科导师的杰出团队下了解IRD的视网膜功能障碍， 候选人科学独立的目标。该提案将利用候选人的研究 神经科学培训和IRD和玻璃体视网膜手术的临床研究金培训 在临床视网膜电生理学和精神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 McAnany博士）、以及单细胞电生理学和遗传学（Neal McAnany博士）。 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 伦理学基础和转化研究。眼科的制度环境 伊利诺伊大学芝加哥分校的视觉科学，其杰出的视觉科学家和 优秀的设施，将最大限度地提高候选人的研究和职业发展的成功。

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.