Development of Optic Nerve Relays to Restore Retinofugal Connections

项目摘要/摘要 视神经疾病和视网膜疾病是全世界不可逆转失明的主要原因。目前， 目前还没有恢复视力丧失的治疗方法。全眼移植可以恢复视力，如果神经回路 眼睛和大脑之间的联系可以恢复。这项提议的长期目标是开发治疗方法 使丢失的视黄醇通路再生，并使全眼移植成为可能。在中枢神经系统实验模型中 神经系统损伤，神经干细胞(NSCs)已经被用来形成神经元继电器来修复损伤 连接和功能。初步数据表明，神经干细胞类似地与受损的视觉整合 系统。中心假设是干细胞来源的神经元移植到视神经中可以恢复 通过接收来自眼睛的输入并延伸远距离轴突投射来发挥作用。这项提议将 通过追求以下具体目标来检验这一假设：1)确定要建立的最佳供体细胞类型 视神经中继器，2)结合视神经的基因编辑优化宿主视网膜节细胞的存活 3)评估与终端目标相邻的视神经中继器形成突触的程度。这个 拟议的研究具有重要意义，因为它们开发了一种利用干细胞形成神经元继电器的新用途 实现强大的、远距离轴突再生，并实现全眼移植。积极的翻译 影响是恢复视力的治疗策略的潜在发展，包括全眼 移植。 这笔K08拨款将使Jiun Do，M.D.，Ph.D.博士获得科学培训和专业技能 建立一个专注于视神经再生的研究计划，并成为独立的调查者。 为了促进这一目标的实现，Do博士在加州大学圣地亚哥分校组建了一支出色的指导团队，由以下人员组成 Mark Tuszynski博士，医学博士，脊椎神经再生和神经干细胞治疗专家 和Derek Welsbie博士，医学博士，博士，视网膜神经节细胞变性和神经保护方面的专家。 这是由一个外部临床医生-科学家委员会的补充，该委员会包括何志刚博士、博士和。 Larry Benowitz博士，视神经再生专家和视觉研究的成功科学家。钥匙 这项培训计划的组成部分包括：1)获得开发干细胞的科学和技术专门知识 技术和修改视觉系统，2)正式的教学课程和赠款撰写、伦理、茎方面的培训 细胞生物学和基因编辑，3)为R01提交生成数据，以及4)计划过渡到 通过师徒关系实现独立。这项工作发生在加州大学圣地亚哥分校，一个出色的研究环境和 世界一流的设施，以及在眼科，有良好的记录，生产 成功的临床医生--科学家。结合他在青光眼方面的临床培训，这份职业发展计划 将使Do博士成为领先的临床医生兼科学家，拥有独立的R01资助的研究计划 专注于开发视神经再生、眼睛移植和视力恢复的治疗方法。

Project Summary/Abstract Optic neuropathies and retinal diseases are leading causes of irreversible blindness worldwide. Currently, there are no therapies to restore vision loss. Whole eye transplants could restore vision if the neural circuits between the eye and the brain could be restored. The long-term goal of this proposal is to develop therapies that regenerate lost retinofugal pathways and enable whole eye transplants. In experimental models of central nervous system injury, neural stem cells (NSCs) have been used to form neuronal relays that restore injured connections and function. Preliminary data suggests that NSCs similarly integrate with the injured visual system. The central hypothesis is that stem cell-derived neurons transplanted into the optic nerve can restore function by receiving inputs from the eye and extending long-distance axonal projections. This proposal will test this hypothesis by pursuing the following specific aims: 1) identify the optimal donor cell type to establish optic nerve relays, 2) optimize survival of host RGCs using gene editing in conjunction with an optic nerve relay, and 3) evaluate the degree to which optic nerve relays adjacent to terminal targets form synapses. The proposed studies are significant because they develop a novel use of stem cells to form neuronal relays to achieve robust, long-distance axonal regeneration and enable whole eye transplants. The positive translational impact is the potential development of therapeutic strategies that restore vision, including whole-eye transplants. This K08 grant will allow Dr. Jiun Do, M.D., Ph.D. to obtain the scientific training and professional skills to establish a research program focused on optic nerve regeneration and become an independent investigator. To facilitate achieving this goal, Dr. Do has assembled an exceptional mentoring team at UCSD consisting of Dr. Mark Tuszynski, M.D., Ph.D., an expert in neuroregeneration and neural stem cell therapies in the spinal cord, and Dr. Derek Welsbie, M.D., Ph.D., an expert on retinal ganglion cell degeneration and neuroprotection. This is complemented by an external clinician-scientist committee that includes Drs. Zhigang He, Ph.D. and. Larry Benowitz, Ph.D., experts in optic nerve regeneration and successful scientists in vision research. Key components of this training plan include: 1) acquisition of scientific and technical expertise to develop stem cell technologies and modify the visual system, 2) formal didactic courses and training in grant writing, ethics, stem cell biology, and gene editing, 3) generation of data for an R01 submission, and 4) planned transition to independence through mentorship. This work takes place at UCSD, an outstanding research environment and world class facility, and in the Department of Ophthalmology, which has a strong track record of producing successful clinician-scientists. Combined with his clinical training in glaucoma, this career development plan will allow Dr. Do to become a leading clinician-scientist with an independent R01-funded research program focused on developing therapies for optic nerve regeneration, eye transplantation, and vision restoration.