Development of Optic Nerve Relays to Restore Retinofugal Connections

项目总结/摘要 视神经病变和视网膜疾病是全球不可逆失明的主要原因。目前， 没有恢复视力丧失的疗法。整个眼睛移植可以恢复视力，如果神经回路 眼睛和大脑之间的连接可以恢复。该提案的长期目标是开发治疗方法 再生失去的视网膜分离途径，使整个眼睛移植成为可能。在中枢神经系统的实验模型中， 神经系统损伤后，神经干细胞（NSC）已被用于形成神经元中继， 连接和功能。初步数据表明，神经干细胞同样与受损的视觉整合， 系统中心假设是，干细胞衍生的神经元移植到视神经可以恢复 通过接收来自眼睛的输入并延伸长距离轴突投射来起作用。这项建议会 通过追求以下具体目标来测试该假设：1）鉴定最佳供体细胞类型以建立 视神经中继，2）使用基因编辑结合视神经优化宿主RGC的存活 中继，和3）评估邻近终端目标的视神经中继形成突触的程度。的 这项研究意义重大，因为他们开发了干细胞形成神经元中继的新用途， 实现强大的长距离轴突再生，并使整个眼睛移植。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 K 08基金将允许Jiun Do博士，医学博士，博士获得科学训练和专业技能， 建立专注于视神经再生的研究计划，并成为独立的研究者。 为了促进实现这一目标，杜博士在加州大学圣地亚哥分校组建了一个特殊的指导团队， 博士Mark Tuszynski，医学博士，哲学博士、脊髓神经再生和神经干细胞治疗专家 以及医学博士德里克·威尔斯比，哲学博士、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，其中包括何志刚博士，博士补充。和. 拉里·本诺维茨博士视神经再生专家和视觉研究领域的成功科学家。关键 该培训计划的组成部分包括：1）获取科学和技术专门知识，以开发干细胞 技术和修改视觉系统，2）正式的教学课程和培训，在赠款写作，道德，科学、技术、工程和数学 细胞生物学和基因编辑，3）生成R 01提交的数据，以及4）计划过渡到 通过指导实现独立。这项工作发生在UCSD，一个杰出的研究环境， 世界一流的设施，并在眼科，其中有一个强大的生产记录 成功的临床科学家结合他在青光眼方面的临床培训， 将使杜博士成为一名领先的临床科学家，拥有独立的R 01资助的研究项目 专注于开发视神经再生、眼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.