Pericyte structural plasticity and cerebrovascular health

周细胞结构可塑性与脑血管健康

• 批准号: 9894994
• 负责人: Andy Y Shih
• 金额: $ 56.44万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9894994
• 关键词: Ablation; Acceleration; Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Basement membrane; Biology; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Cells; Cerebral cortex; Cerebrovascular Disorders; Communication; Complement; Data; Development; Disease; Drug or chemical Tissue Distribution; Endothelium; Event; Gene Expression; Genetic; Goals; Health; Histologic; Hypoxia; Image; Impairment; Invaded; Investigation; Knowledge; Life; Light; Maintenance; Measures; Methods; Modeling; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Optics; Oxygen; PDGF inhibition; PDGFRB gene; Peptides; Pericytes; Pharmacology; Physiological; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Process; Regulation; Reporting; Resolution; Role; Severities; Signal Pathway; Signal Transduction; Stretching; Structure; Synapses; Testing; Theft; Tissues; Work; age related; aged; aging brain; capillary bed; cell type; cerebral capillary; cerebrovascular; cerebrovascular health; genetic manipulation; hemodynamics; imaging probe; improved; in vivo; in vivo calcium imaging; in vivo imaging; in vivo two-photon imaging; innovation; insight; knock-down; middle age; multidisciplinary; neurovascular; novel; platelet-derived growth factor BB; preservation; recruit; relating to nervous system; repaired; response; synaptic function; tissue oxygenation; two photon microscopy; two-photon

Project Summary Pericytes are specialized mural cells in the basement membrane of brain capillaries. Their contact and communication with the endothelium is critical for multiple aspects of vascular function, including control of microvascular blood flow and blood-brain barrier integrity. There is significant evidence that increased loss of pericytes occurs during Alzheimer's disease and Alzheimer's-related dementias, and that this loss causes accelerated degradation of microvascular integrity, leading to neuronal dysfunction. Preserving pericyte- endothelial contact may therefore improve cerebrovascular function in these neurodegenerative diseases. However, there remain fundamental gaps in knowledge on how the adult brain responds to and recovers from pericyte loss in vivo. We recently discovered that pericytes of the brain undergo a repair strategy to maintain coverage of the endothelium in the event of pericyte loss (Berthiaume et al. Cell Reports, 2018, 22(1):8-16). Pericytes can structurally remodel their far-reaching processes to invade endothelial regions that lack pericyte contact. The goal of this project is to investigate this novel facet of brain pericyte biology and its role in maintenance of capillary function. Our innovative approach will assess the effect of pericyte loss and repair in a completely physiological setting. We will use high-resolution, in vivo two-photon microscopy to image and selectively ablate pericytes, while assessing capillary hemodynamics, tissue oxygenation, and neural synaptic activity. This approach provides an exceptionally clear view of how the brain responds to pericyte loss, and the reparative responses that are mounted over days. In Aim 1, we will determine how the pericyte remodeling mechanism manages graded increases in severity of pericyte loss. We will examine the physiological consequence of this pericyte loss on capillary flow, structure and integrity, and determine whether the repair capacity is diminished with increasing age. In Aim 2, we will examine how pericyte loss alters the microstructure of tissue oxygen distribution and neuronal synaptic function using novel imaging probes. In Aim 3, we will determine whether pericyte remodeling is altered by activation or inhibition of PDGF-B/PDGFRβ, a key signaling pathway for developmental recruitment of pericytes to their peri-endothelial niche. If successful, our aims will establish whether it is useful to restore pericyte coverage in conditions such as Alzheimer's disease and related dementias. We will obtain information on how selective pericyte loss in adult and aged brain affects the dynamics of capillary function. Finally, we will establish novel methods to quantify and manipulate pericyte remodeling, allowing the phenomenon to be studied broadly in other models of cerebrovascular disease.

项目摘要 周细胞是脑毛细血管基底膜的专门壁细胞。他们的联系和 与内皮的通信对于血管功能的多个方面至关重要，包括控制 微血管血流和血脑屏障完整性。有大量证据表明，损失的损失增加 周细胞发生在阿尔茨海默氏病和阿尔茨海默氏症相关的痴呆症期间，这种损失导致 微血管完整性的加速降解，导致神经元功能障碍。保存周细胞 - 因此，内皮接触可以改善这些神经退行性疾病中的脑血管功能。 但是，关于成年大脑如何反应和从 体内周细胞损失。我们最近发现，大脑周细胞经历维护策略以维持 在周围损失的情况下，内皮的覆盖范围（Berthiaume等人。细胞报告，2018，22（1）：8-16）。 周细胞可以在结构上重塑其深远的过程，以入侵缺乏周细胞的内皮区域 接触。该项目的目的是调查这个新颖的脑周围生物学的新方面及其在 维护毛细管功能。我们的创新方法将评估周细胞损失和维修的影响 完全物理设置。我们将使用高分辨率的体内两光子显微镜进行图像和 在评估毛细血管血液动力学，组织氧合和神经突触的同时，有选择地烘烤周细胞 活动。这种方法对大脑如何应对周细胞的损失有一个异常清晰的看法，以及 在几天内安装的修复响应。在AIM 1中，我们将确定周细胞的重塑 机制管理周细胞损失的严重程度的分级增加。我们将检查生理 这种周细胞损失对毛细血管流，结构和完整性的结果，并确定维修是否 随着年龄的增长，容量会降低。在AIM 2中，我们将研究周细胞损失如何改变 使用新成像问题的组织氧分布和神经元突触功能的微观结构。目标 3，我们将确定周细胞重塑是否通过激活或抑制PDGF-B/PDGFRβ（a）改变 将周细胞生长募集到其周围的小众生殖位的关键信号通路。如果成功， 我们的目标将确定在阿尔茨海默氏症等条件下恢复周细胞覆盖范围是否有用 疾病和相关痴呆症。我们将获得有关成人和老年人选择性周细胞损失的信息 大脑会影响毛细血管功能的动力学。最后，我们将建立新颖的方法来量化和 操纵周细胞重塑，使现象可以广泛研究其他模型 脑血管疾病。