Investigation of the neuroimmune axis in retinal regeneration.

项目总结/摘要 视力丧失对个人的生活质量有着毁灭性的影响。大多数致盲性疾病都是由于 视网膜神经元的数量治疗威胁视力的疾病的一个有希望的策略是利用再生的 视网膜内细胞的潜能。Müller胶质细胞（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，我们已经开发出策略，在神经发生学上重新编程MG， 成年小鼠通过过度表达转录因子Ascl 1在MG。值得注意的是，Ascl 1的治疗 过表达，结合NMDA诱导的视网膜损伤和组蛋白脱乙酰酶（HDAC）抑制， 导致MG在成年哺乳动物视网膜中再生功能性神经元。虽然这是一个重大进展， 为了实现MG的治疗潜力，只有一部分MG成功地重编程为神经源性的， 而MG的另一个子集表达与炎症过程相关的基因。我们 假设伴随神经细胞损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， 显著改善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组成部分。然而，人们对此知之甚少。 神经免疫界面在视网膜修复策略中的作用，如内源性再生。该提案概述了 研究，以更好地了解MG介导的视网膜再生过程中的神经免疫轴， 免疫调节策略，以提高哺乳动物视网膜的再生能力。数据 在这个提案中产生的将是基础博士托德的最终目标，成为一个独立的 调查员在K99部分，托德博士将扩大他的技术和理论专长， 神经免疫学，以实现他的目标，研究免疫神经胶质细胞的相互作用在视网膜再生。新 将与神经免疫学研究人员建立合作关系，进一步的培训活动将 准备博士托德成为一个成功的调查员在外地。本提案的培训部分将 我在华盛顿大学有一个很好的位置，那里有很好的研究设备和师资 专业知识，以协助申请人的目标的实现。

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.