The Role of Purinergic Signaling in Microglia Birth and Maturation in the Adult Brain

嘌呤能信号在成人大脑小胶质细胞出生和成熟中的作用

• 批准号: 10312432
• 负责人: Monique Shanice Mendes
• 金额: $ 7.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312432
• 关键词: Role; Purinergic; Signaling; Microglia; Birth

Project Summary. Microglia are the brain’s immune cells and have long been appreciated for their critical roles during brain injury and disease. Recent studies, however, have demonstrated that microglia have important roles in the absence of pathology and serve to maintain brain homeostasis, support developing neurons and aid in the remodeling of neural circuitry during development and plasticity. This makes microglia a therapeutic target for diseases in which neural circuits either develop or remodel inappropriately. Despite their importance in brain health and disease, very little is known about how microglia self-maintain after they colonize the brain during development. This knowledge is fundamental to understanding how microglia maintain their functions throughout the lifespan. While microglia are long-lived cells, depletion methods have demonstrated that the adult microglial population can be rapidly reconstituted by the proliferation of resident cells. Because these studies have been carried out in fixed tissue the dynamics and mechanisms of this process are unclear. I propose to determine how microglia are born and mature in vivo. I will also explore the role of the purinergic receptor, P2Y12 in this process. I hypothesize that microglia are born by the division of single microglia and depend on purinergic signaling to rapidly differentiate morphologically and functionally to perform their physiological roles in the brain. In order to test this hypothesis, I will address two related but independent aims. In Aim 1, I have started to test the hypothesis that microglia repopulate from rapid division of single surviving microglia under normal conditions and after experimental depletion. I have also shown that microglia are critical to experience- dependent plasticity in the adult visual cortex. In Aim 2, I will test the hypothesis that the physiological attributes of microglia such as process motility and microglia-synapse interactions return to baseline soon after microglia are born in the adult. I will also explore whether P2Y12 signaling contributes to the maturation of these attributes in newly-born adult microglia. Lastly, I will examine how rapidly newly-born microglia acquire their functions that support experience-dependent plasticity in the visual cortex. Together these two aims characterize how microglia proliferate and maintain homeostasis in the adult cortex. Thus, this proposal embodies a new set of techniques that allows the close monitoring of the self-renewal dynamics of microglia. The training I will obtain in graduate school while performing the first to aims, will prepare me for my postdoctoral studies in Aim 3, where I will carry out collaborative work to determine therapeutic targets for the treatment of neurodevelopmental disorders.

项目摘要。小胶质细胞是大脑的免疫细胞，长期以来因其关键作用而受到赞赏 在脑损伤和疾病期间。然而，最近的研究表明，小胶质细胞具有重要作用 在没有病理学的情况下，可以维持大脑体内稳态，支持发展神经元并帮助 在发育和可塑性过程中进行神经元电路的重塑。这使小胶质细胞成为 神经回路的疾病不适当地发育或重塑。尽管它们在大脑中的重要性 健康和疾病，关于小胶质细胞在在大脑期间定居大脑后如何自我维护的人鲜为人知 发展。这些知识是了解小胶质细胞如何保持其功能的基础 寿命。虽然小胶质细胞是长寿命的细胞，但部署方法证明了成年小胶质细胞 人口可以通过居民细胞的扩散迅速重组。因为这些研究已经 在固定组织中进行的动力学和机制尚不清楚。我建议确定如何 小胶质细胞在体内出生并成熟。我还将探讨嘌呤能受体P2Y12在此过程中的作用。 我假设小胶质细胞是由单胶质细胞的分裂而诞生的，依赖嘌呤能 发出信号以迅速在形态和功能上迅速区分以在 大脑。为了检验这一假设，我将解决两个相关但独立的目标。在AIM 1中，我有 开始检验以下假设：小胶质细胞从单一幸存的小胶质细胞的快速分裂中重生 正常条件和实验耗竭后。我还表明，小胶质细胞对于经验至关重要 - 成人视觉皮层的依赖性可塑性。在AIM 2中，我将测试物理属性的假设 小胶质细胞（例如过程运动性和小胶质细胞互动相互作用 出生于成年人。我还将探讨P2Y12信号是否有助于这些属性的成熟 在新生的成年小胶质细胞中。最后，我将研究新生的小胶质细胞迅速获得其功能 在视觉皮层中支持经验依赖的可塑性。这两个目的共同表征了小胶质细胞 在成年皮层中增殖并维持稳态。那，该提案体现了一套新的技术 这允许密切监视小胶质细胞的自我更新动力学。我将在研究生中获得的培训 学校在第一个瞄准目标的同时，我会为我在AIM 3的博士后学习做好准备，我将在那里携带 为了确定治疗神经发育障碍的治疗靶点的协作工作。