Microglial plasticity mechanisms in the developing retina

项目总结 小胶质细胞是一种吞噬细胞，在视网膜发育和眼部疾病中起着多种关键作用。在……里面 类似地，它们在功能和分子状态上表现出显著的多样性。这表明，一个多样化的 视网膜需要一系列小胶质细胞亚型，但将小胶质细胞状态与其功能联系起来的分子 仍然不为人所知。这里的目标是确定指定小胶质细胞状态的分子和细胞机制 视网膜的变化。中心假设是小胶质细胞吞噬状态是由神经元通过 特定的神经元衍生受体-配体对-信号调节蛋白α(Sirpα)和CD47.这种受体- 配基对在小胶质细胞中构成了关键的“不要吃我”的反吞噬信号。初步数据出人意料地显示， 然而，神经元来源Sirpα对调节小胶质细胞的吞噬功能和吞噬功能也是至关重要的 州政府。神经元Sirpα似乎通过充当诱骗受体来阻止小胶质细胞CD47-Sirpα来实现这一点 信号，从而允许小胶质细胞在视网膜发育过程中吞噬。要了解这些机制， 以此来确定小胶质细胞的吞噬状态，并检验神经元Sirpα-CD47信号假说， 提出了三个具体目标。首先，我们将确定神经元sirpα何时以及如何改变小胶质细胞。 多样性和可塑性。这些研究将确定神经元Sirpα是否通过 调节它们的成熟或通过发育后的变化。第二，我们将定义小胶质细胞是如何 调和促进不同生理状态的相互冲突的线索。这些实验将导致 在小胶质细胞状态选择过程中，建立“吃我”和“不要吃我”线索之间的关系。第三，我们 将确定依赖于Sirpα驱动的小胶质细胞状态变化的发育事件。这一目标将 确定由神经元Sirpα驱动的小胶质细胞状态变化的功能后果。特别是，我们将测试 星形胶质细胞的死亡是否依赖于神经元Sirpα信号，这一假说得到了我们初步数据的支持。 这项工作将具有重要意义，因为识别出一种神经元衍生的机制，它决定了小胶质细胞的状态 可塑性是意想不到的。因此，这项工作的完成将改变我们理解如何发展的方式 信号对小胶质细胞的结果进行编程。这项研究还将为新的治疗方案奠定基础 改变视网膜小胶质细胞的状态和功能。

PROJECT SUMMARY Microglia are phagocytic cells that play multiple critical roles in retinal development and ocular diseases. In parallel, they display remarkable diversity in their functional and molecular states. This suggests that a diverse portfolio of microglial subtypes is needed in the retina, but the molecules that link microglia state to their function remain unknown. The objective here is to identify molecular and cellular mechanisms that specify microglia state changes in the retina. The central hypothesis is that microglia phagocytic states are specified by neurons via a particular neuron-derived receptor-ligand pair – signal regulatory protein alpha (SIRPα) and CD47. This receptor- ligand pair constitutes a key “don’t eat me” anti-phagocytic signal in microglia. Preliminary data surprisingly show, however, that neuron-derived SIRPα is also crucial for regulating microglial phagocytic function and phagocytic state. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47-SIRPα signaling, thereby permitting microglia phagocytosis during retinal development. To understand the mechanisms by which microglia phagocytic states are specified, and to test the neuronal SIRPα-CD47 signaling hypothesis, three Specific Aims are proposed. First, we will determine when and how neuronal SIRPα alters microglia diversity and plasticity. These studies will establish whether neuronal SIRPα alters microglia state by regulating their maturation or by post-developmental changes. Second, we will define how microglia reconcile conflicting cues that promote different physiological states. These experiments will causally establish the relationship between ‘eat me’ and ‘don’t eat me’ cues during microglia state selection. Third, we will Identify developmental events that depend on SIRPα-driven microglial state changes. This aim will define functional consequences of microglial state changes driven by neuronal SIRPα. In particular, we will test whether astrocyte death depends on neuronal SIRPα signaling, a hypothesis supported by our preliminary data. This work will be significant because identification of a neuron-derived mechanism that dictates microglia state plasticity is unexpected. Thus, completion of this work will change the way we understand how developmental signals program microglia outcomes. This study will also lay the groundwork for new therapeutic options to modify retina microglia state and function.