Macrophage Determinants of Retinal Regeneration

项目总结：视网膜再生的巨噬细胞决定因素 本建议的目的是了解小胶质细胞和巨噬细胞的个体发育、动力学和 内源性在视网膜退化和再生中的作用--以脊椎动物斑马鱼为模型 在遭受各种侮辱后能够强健地再生视网膜的有机体。人类并不拥有这一点 无论是在急性视网膜损伤的情况下还是在视网膜神经退行性疾病的情况下， 尽管小胶质细胞和巨噬细胞是神经元死亡反应的积极参与者，而且 巨噬细胞能够推动周围组织的伤口愈合。此外，在某些情况下，小胶质细胞和 巨噬细胞似乎在病理中起作用，尽管这种病理作用的调节没有。 已经实现了。为了提供未来的治疗和再生策略来支持内源性 小胶质细胞/巨噬细胞特有的机制，积极调节再生和/或传递的结果 通过战略操纵来执行这些功能的能力，更多的基础知识是 必填项。我们认为，对小胶质细胞和巨噬细胞功能的彻底了解 强健的视网膜再生(特别是斑马鱼)将揭示小胶质细胞和巨噬细胞的功能， 最终被利用来减轻神经炎症和支持人类视网膜再生的尝试。 我们已发表的和初步的数据表明，在斑马鱼中，视网膜驻留的小胶质细胞和额外的 视网膜来源的巨噬细胞存在于急性视网膜损伤后的退化和再生的视网膜组织中。 细胞毒性损伤，这些小胶质细胞/巨噬细胞与再生的Müler胶质细胞密切相互作用 作为再生神经元的来源。活动期间小胶质细胞/巨噬细胞的转录图谱 Müler胶质细胞介导的再生提示小胶质细胞/巨噬细胞功能的变化 州政府。我们的初步数据还表明，将小胶质细胞表型改变为促炎状态可能 会导致神经元退化。我们假设小胶质细胞和巨噬细胞在 在塑造视网膜退化和再生的结果方面起着重要作用。以下具体目标将受到考验 这个假说。1.测定小胶质细胞和巨噬细胞异质性的程度和持续时间 视网膜损伤。2.确定促炎巨噬细胞如何影响视网膜变性和再生。3. 测定小胶质细胞和巨噬细胞在视网膜再生中的内源性功能(S)。由此得出的结论 该提案将(I)为未来的研究提供关键的知识和工具，以识别小胶质细胞与 巨噬细胞特异的分子机制导致视网膜变性和成功再生 (2)促进比较研究，以确定决定结果的关键因素和机制(病理学 与哺乳动物相比，斑马鱼的视网膜损伤后的视网膜损伤。总体而言，这一新的 知识将为成功设计和应用治疗策略提供基础 人类视网膜损伤和疾病。

Project Summary: Macrophage Determinants of Retinal Regeneration The objective of this proposal is to understand microglia and macrophage ontogeny, dynamics, and endogenous roles in retinal degeneration and regeneration using the zebrafish as a model, a vertebrate organism capable of robust retinal regeneration following a variety of insults. Humans do not possess this regenerative capacity both in contexts of acute retinal damage or in neurodegenerative diseases of the retina, although microglia and macrophages are active participants in the response to neuronal death, and macrophages are able to drive wound healing in peripheral tissues. Further, in some contexts, microglia and macrophages appear to contribute to pathology, though modulation of such pathological contributions has not been achieved. In order to provide future therapeutic and regenerative strategies to support endogenous microglia/macrophage-specific mechanisms that positively regulate the outcome of regeneration and/or impart the capacity to perform such functions through strategic manipulation, more foundational knowledge is required. We propose that a thorough understanding of microglia and macrophage functions in a system of robust retinal regeneration (specifically, the zebrafish) will reveal microglia and macrophage functions that can ultimately be harnessed to mitigate neuroinflammation and support attempts at retinal regeneration in humans. Our published and preliminary data indicate that in zebrafish, both retinal resident microglia and extra- retinally derived macrophages are present in degenerating and regenerating retinal tissue following an acute cytotoxic lesion, and these microglia/macrophages intimately interact with regenerative Müller glia, the cell type acting as the source of regenerated neurons. Transcriptional profiling of microglia/macrophages during active Müller glia-mediated regeneration indicates functional changes in microglia/macrophages compared to steady- state. Our preliminary data also indicate that altering microglial phenotype to a pro-inflammatory state may contribute to neuronal degeneration. We hypothesize that microglia and macrophages perform crucial functions in shaping the outcome of retinal degeneration and regeneration. The following Specific Aims will test this hypothesis. 1. Determine the extent and duration of microglia and macrophage heterogeneity following retinal injury. 2. Determine how pro-inflammatory macrophages affect retinal degeneration and regeneration. 3. Determine endogenous function(s) of microglia and macrophages in retinal regeneration. Findings from this proposal will (I) provide crucial knowledge and tools towards future research to identify microglia vs. macrophage-specific molecular mechanisms underlying retinal degeneration and successful regeneration and (II) facilitate comparative studies to identify key factors and mechanisms that determine outcome (pathology vs. regeneration) following retinal damage in zebrafish compared to mammals. Collectively, this new knowledge will provide foundations towards successful design and application of therapeutic strategies for human retinal damage and disease.