Investigation of the neuroimmune axis in retinal regeneration.

项目摘要/摘要 失明会对个人的生活质量产生毁灭性的影响。大多数致盲疾病都是由丧失引起的 视网膜中的神经元。治疗威胁视力的疾病的一个很有希望的策略是利用再生的 视网膜内细胞的潜能。Müler glia(MG)在低等脊椎动物中具有非凡的能力 再生视网膜神经元。然而，在包括人类在内的哺乳动物视网膜中，MG无法取代 神经元因损伤或疾病而丧失。最近，我们已经开发了一些策略来对MG进行神经重新编程 成年小鼠在MG中过表达转录因子Ascl1。值得注意的是，Ascl1的治疗 过度表达，再加上NMDA诱导的视网膜损伤和组蛋白脱乙酰酶(HDAC)抑制， 使MG在成年哺乳动物视网膜中再生功能神经元。虽然这是一个重大的进步 为了实现MG的治疗潜力，只有一部分MG成功地重新编程为神经源性 而MG的另一个亚群表达与炎症过程相关的基因。我们 假设伴随神经细胞丢失的炎症限制了神经细胞的再生潜力 Mg.事实上，我们最近发现，切除小胶质细胞，视网膜的内源性免疫细胞， 极大地改善了MG介导的视网膜再生。这一发现表明，神经免疫系统是一种 哺乳动物视网膜再生反应的关键成分。然而，人们对此知之甚少 神经免疫接口在视网膜修复策略中的作用，如内源性再生。这份提案概述了 更好地了解MG介导的视网膜再生过程中的神经免疫轴并发展的研究 提高哺乳动物视网膜再生能力的免疫调节策略。数据 在这项提案中产生的将是托德博士成为独立医生的最终目标的基础 调查员。在K99部分，托德博士将在以下方面扩展他的技术和理论专长 神经免疫学，以实现他的目标，研究视网膜再生过程中的免疫-神经胶质相互作用。新的 将与神经免疫学的研究人员建立合作关系，并将开展进一步的培训活动 让托德博士做好准备，成为该领域的一名成功的调查员。本建议书的培训部分将需要 华盛顿大学，它提供了获得研究设备和教职员工的特殊途径 帮助申请人实现目标的专业知识。

Project Summary/Abstract Loss of vision has a devastating impact on an individual's quality of life. Most blinding diseases result from loss of neurons in the retina. A promising strategy to treat sight-threatening diseases, is to harness the regenerative potential of cells within the retina. Müller glia (MG), possess an extraordinary capacity in lower vertebrates to regenerate retinal neurons. However, in mammalian retinas, including humans, MG are unable to replace neurons lost to injury or disease. Recently, we have developed strategies to neurogenically reprogram MG in adult mice by overexpressing the transcription factor Ascl1 in MG. Remarkably, the treatment of Ascl1 overexpression, combined with NMDA-induced retinal damage and histone deacetylase (HDAC) inhibition, causes MG to regenerate functional neurons in the adult mammalian retina. While this is significant progress towards realizing the therapeutic potential of MG, only a subset of MG successfully reprogram into neurogenic progenitors while another subset of MG express genes associated with inflammatory processes. We hypothesized that the inflammation that accompanies neuronal cell loss restricts the regenerative potential of MG. Indeed, we recently found that ablation of microglia, the endogenous immune cell of the retina, dramatically improved MG-mediated retinal regeneration. This finding implicates the neuroimmune system as a key component of the regenerative response of the mammalian retina. However, little is known about the neuroimmune interface in retinal repair strategies such as endogenous regeneration. This proposal outlines studies to better understand the neuroimmune axis during MG-mediated retinal regeneration and to develop immunomodulation strategies to improve the regenerative capacity of the mammalian retina. The data generated in this proposal will be foundational to Dr. Todd's ultimate goal of becoming an independent investigator. During the K99 portion, Dr. Todd will expand his technical and theoretical expertise in neuroimmunology to accomplish his aims studying immune-glial interactions during retinal regeneration. New collaborations will be established with investigators in neuroimmunology and further training activities will prepare Dr. Todd to become a successful investigator in the field. The training portion of this proposal will take place at the University of Washington, which offers exceptional access to both research equipment and faculty expertise to assist in the accomplishment of the applicant's goals.