Pericyte structural plasticity and cerebrovascular health

项目摘要 周细胞是脑毛细血管基底膜上的特化壁细胞。它们的接触和 与内皮的通信对于血管功能的多个方面是至关重要的，包括对血管内皮细胞的控制。 微血管血流和血脑屏障完整性。有大量证据表明， 周细胞发生在阿尔茨海默病和阿尔茨海默病相关的痴呆症，这种损失导致 微血管完整性加速降解，导致神经元功能障碍。保存周细胞- 因此，内皮接触可改善这些神经退行性疾病中的脑血管功能。 然而，关于成人大脑如何应对和恢复的知识仍然存在根本性的差距。 体内周细胞丢失。我们最近发现，大脑周细胞进行修复策略，以维持 在周细胞损失的情况下覆盖内皮（Berthiaume等人Cell Reports，2018，22（1）：8-16）。 周细胞可以在结构上重塑其深远的过程，侵入缺乏周细胞的内皮区域 contact.这个项目的目标是研究大脑周细胞生物学的这个新方面及其在 维持毛细血管功能。我们的创新方法将评估周细胞损失和修复的影响， 完全的生理环境。我们将使用高分辨率，在体内双光子显微镜成像， 选择性消融周细胞，同时评估毛细血管血流动力学、组织氧合和神经突触 活动这种方法提供了一个非常清晰的视图，大脑如何响应周细胞的损失， 修复性反应持续了数天在目标1中，我们将确定周细胞重塑 机制管理周细胞损失严重程度的分级增加。我们将研究 结果，这种周细胞损失对毛细血管流动，结构和完整性，并确定是否修复 能力随着年龄的增长而减弱。在目标2中，我们将研究周细胞损失如何改变 组织氧分布和神经元突触功能的显微结构使用新的成像探针。在Aim中 3，我们将确定周细胞重塑是否通过激活或抑制PDGF-B/PDGFRβ而改变， 周细胞向其内皮周围小生境发育募集的关键信号传导途径。如果成功， 我们的目标是确定在阿尔茨海默氏症等疾病中恢复周细胞覆盖是否有用 疾病和相关的痴呆症。我们将获得关于成人和老年人选择性周细胞丢失的信息， 大脑影响毛细血管功能的动力学。最后，我们将建立新的方法来量化和 操纵周细胞重塑，允许在其他模型中广泛研究这种现象。 脑血管疾病

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.