Microglial plasticity mechanisms in the developing retina

视网膜发育中的小胶质细胞可塑性机制

基本信息

批准号：
10716629
负责人：
Melanie A Samuel
金额：
$ 52.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716629
关键词：
Adopted Anus Astrocytes Biological Assay Blindness CD47 gene Cell physiology Cells Cessation of life Cues Data Development Diabetic Retinopathy Disease Disease Progression Eating Event Excision Eye diseases Genetic Genetic Transcription Glaucoma Goals Health Heterogeneity Immune Immune signaling Knowledge Ligands Link Macrophage Mediating Microglia Molecular Mus Neurons Outcome Pathology Pathway interactions Phagocytes Phagocytosis Phagocytosis Inhibition Phosphatidylserines Physiological Play Population Property Retina Retinal Degeneration Retinal Diseases Role SHPS-1 protein Signal Transduction Specific qualifier value Synapses Testing Therapeutic Time Variant Vision Work cell motility cell regeneration cell type experimental study functional plasticity genetic manipulation molecular imaging nanoscale neonatal mice neurotransmission novel novel therapeutics overexpression permissiveness prevent programs receptor retinal regeneration single cell sequencing

项目摘要

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.

项目摘要小胶质细胞是吞噬细胞，在残留发育和眼部疾病中起多个关键作用。在平行于其功能和分子状态显示出显着的多样性。这表明潜水员在视网膜中需要小胶质细胞的组合，但是将小胶质细胞状态与其功能联系起来的分子仍然未知。这里的目的是确定指定小胶质细胞状态的分子和细胞机制视网膜变化。中心假设是神经元通过A指定的小胶质细胞状态特定的神经衍生的受体配体 - 信号调节蛋白α（SIRPα）和CD47。这个受体 - 配体对构成了小胶质细胞中的关键“不要吃我”的抗吞噬信号。初步数据令人惊讶地显示，但是，神经衍生的SIRPα对于调节小胶质细胞功能和吞噬细胞也至关重要状态。神经元SIRPα似乎通过充当诱饵受体来预防小胶质细胞CD47-SIRPα来实现这一目标信号传导，从而在视网膜发育过程中允许小胶质细胞吞噬作用。了解机制通过指定小胶质细胞状态的小胶质细胞，并测试神经元SIRPα-CD47信号传导假设，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是否通过调节其成熟或通过发育后变化。其次，我们将定义小胶质细胞调和相互冲突的线索，以促进不同的身体状态。这些实验将有因果关系在小胶质细胞选择期间，建立“吃我”和“不要吃我”线索之间的关系。第三，我们将确定取决于SIRPα驱动的小胶质细胞变化的发展事件。这个目标定义由神经元SIRPα驱动的小胶质状状态变化的功能后果。特别是，我们将测试星形胶质细胞死亡是否取决于神经元SIRPα信号传导，这是我们初步数据支持的假设。这项工作将是重要的，因为鉴定了决定小胶质细胞状态的神经衍生机制可塑性是出乎意料的。这项工作的完成将改变我们了解发展的方式信号计划小胶质细胞结果。这项研究还将为新的治疗选择奠定基础修改视网膜小胶质细胞状态和功能。