Microglial-Neurovascular Dynamics and Regulation of Neurovascular Structure and Function

小胶质细胞神经血管动力学以及神经血管结构和功能的调节

• 批准号: 10274632
• 负责人: Ukpong Bassey Eyo
• 金额: $ 40.14万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274632
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Astrocytes; Blood; Blood Vessels; Body Weight; Brain; Brain Diseases; Brain Injuries; Brain Pathology; CSF1R gene; Calcium Signaling; Caliber; Cells; Cerebrovascular Circulation; Cerebrovascular system; Confocal Microscopy; Consumption; Data; Development; Functional disorder; Glucose; Health; Homeostasis; Immune; Mediating; Microglia; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Organ; Oxygen; Participant; Pathogenesis; Pathology; Pharmacogenetics; Pharmacology; Physiology; Population; Process; Regulation; Research; Role; Signal Transduction; Structure; TREM2 gene; Testing; Tissues; Transgenic Mice; Vasodilation; abeta accumulation; brain dysfunction; cell type; cerebrovascular; genome wide association study; in vivo two-photon imaging; insight; interest; macrophage; mouse model; neurovascular; novel; receptor; response; risk variant; two-photon

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.

项目摘要 大脑占身体重量的2%，但使用身体能量的20%，这是从大脑中观察到的。 通过神经血管系统的密集网络输送血液。神经血管功能对于 最佳的脑功能和改变的神经血管功能有助于或脑病理学。小胶质细胞吃大脑- 常驻免疫细胞对脑损伤和疾病作出反应，但它们与血管系统的相互作用 探索得不好。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。具体来说，我发现大约三分之一的小胶质细胞 通过它们的细胞体与神经血管系统物理地相互作用， 流程.有趣的是，Trem 2（一种AD的小胶质细胞特异性风险基因）的缺乏导致AD的显著性降低。 增加小胶质细胞-血管相互作用。最后，CSF 1 R表达细胞的药理学消除 如小胶质细胞导致血管尺寸和脑血流量增加，表明 血管系统上的小胶质细胞在这个项目中，我将进一步调查这一点，通过（i）确定具体的角色， 小胶质细胞调节血管结构和功能;（ii）确定星形胶质细胞终足的需求 介导小胶质细胞依赖性血管结构和功能调节的钙信号传导，和（iii） 确定TREM 2在小胶质细胞-血管相互作用中的作用，包括AD中的血管淀粉样蛋白沉积。这些 这些研究将深入了解小胶质细胞调控的细胞、分子和机制基础， 神经血管结构和功能。