Pericyte structural plasticity and cerebrovascular health

项目摘要 周细胞是一种特殊的壁细胞，位于脑毛细血管基底膜上。他们的联系方式和 与内皮细胞的沟通对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的完整性。有重要证据表明， 周细胞在阿尔茨海默病和阿尔茨海默氏症相关的痴呆期间发生，这种缺失导致 微血管完整性加速退化，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的脑血管功能。 然而，关于成人大脑如何反应和恢复的知识仍然存在根本空白 活体内周细胞丢失。我们最近发现，大脑的周细胞经历一种修复策略来维持 周细胞丢失时内皮细胞的覆盖率(Berthiaume等人细胞报告，2018，22(1)：8-16)。 周细胞可以在结构上重塑其影响深远的过程，以侵入缺乏周细胞的内皮区域。 联系。该项目的目标是研究脑周细胞生物学的这一新方面及其在 维持毛细血管功能。我们的创新方法将评估周细胞丢失和修复的影响 完全生理性的环境。我们将使用高分辨率的活体双光子显微镜来成像和 选择性地消融周细胞，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角，了解大脑如何应对周细胞丢失，以及 几天后积累起来的修复性反应。在目标1中，我们将确定周细胞如何重塑 机制管理周细胞丢失严重程度的分级增加。我们会检查生理上的 这种周细胞丢失对毛细血管流动、结构和完整性的后果，并决定是否修复 随着年龄的增长，能力会减弱。在目标2中，我们将研究周细胞丢失如何改变 使用新型成像探针研究组织氧分布和神经元突触功能的微观结构。在AIM 3，我们将确定周细胞重塑是通过激活还是抑制PDGF-B/PDGFFRβ，a 周细胞发育募集到其内皮周壁龛的关键信号通路。如果成功， 我们的目标将确定在阿尔茨海默氏症等情况下恢复周细胞覆盖率是否有用 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丢失的信息 大脑影响毛细血管功能的动态变化。最后，我们将建立新的方法来量化和 操纵周细胞重塑，使这一现象在其他模型中得到广泛研究 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.