Microglial-Neurovascular Dynamics and Regulation of Neurovascular Structure and Function

项目摘要 大脑占身体重量的2%，但从大脑的角度观察，大脑消耗的能量占身体能量的20% 通过神经血管系统的致密网络输送血液。神经血管功能对 最佳的大脑功能和改变的神经血管功能有助于或大脑病理。小胶质细胞吞噬了大脑- 对脑损伤和疾病做出反应的常驻免疫细胞，但它们与血管系统的相互作用 没有得到很好的探索。在我的初步数据中，我广泛地描述了小胶质细胞与 健康大脑中的神经血管系统。具体地说，我发现大约三分之一的小胶质细胞种群 它们通过细胞体与神经血管系统进行物理上的相互作用，这些细胞体比它们的 流程。有趣的是，阿尔茨海默病的小胶质细胞特异性风险基因TREM2的缺失会导致显著的 小胶质细胞-血管相互作用增加。最后，药物消除表达CSF1R的细胞 如小胶质细胞导致血管大小和脑血流量增加，提示在 血管系统上的小胶质细胞。在这个项目中，我将通过(I)确定特定角色来进一步研究这一点 小胶质细胞在调节血管结构和功能中的作用；(Ii)确定星形细胞终足的需求 钙信号在介导小胶质细胞依赖的血管结构和功能调节中的作用 确定TREM2在小胶质细胞-血管相互作用中的作用，包括AD中血管淀粉样蛋白的沉积。这些 研究将提供对小胶质细胞调节的细胞、分子和机制基础的见解。 神经血管的结构和功能。

Project Summary The brain makes up 2% of the body’s weight but uses 20% of the body’s energy that is observed from the delivery of blood through the dense network of the neurovasculature. Neurovascular function is critical for optimal brain function and altered neurovascular function contributes or brain pathology. Microglia ate brain- resident immune cells that respond to brain injuries and disease but their interactions with the vasculature has been poorly explored. In my preliminary data, I extensively characterized microglial interactions with the neurovasculature in the healthy brain. Specifically, I have found that about a third of the microglia population physically interact with the neurovasculature through their cell bodies which are more stationary than their processes. Interestingly, a deficiency of Trem2, a microglial-specific risk gene for AD, results in a significant increase in microglial-vascular interactions. Finally, pharmacological elimination of CSF1R-expressing cells such as microglia resulted in increased vascular size and cerebral blood flow suggesting modulatory roles for microglia on the vasculature. In this project, I will further investigate this by (i) determining specific roles for microglia in regulating vascular structure and function; (ii) determining the requirement for astrocytic endfeet calcium signaling in mediating microglial-dependent vascular structure and functional regulation, and (iii) determine TREM2 roles in microglial-vascular interactions including vascular amyloid deposition in AD. These studies will provide insights into the cellular, molecular and mechanistic basis of microglial regulation of neurovascular structure and function.