Diversity Supplement (Qudrat Abdulwahab) for Role of pericyte nanotubes in age-related neurovascular dysfunction

周细胞纳米管在年龄相关神经血管功能障碍中的作用的多样性补充剂（Qudrat Abdulwahab）

基本信息

批准号：
10702114
负责人：
Melanie A Samuel
金额：
$ 11.96万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2024-04-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease associated dementias are characterized by marked alterations in neural function and associated cognitive decline. Though changes to neurons themselves are important, recent findings by our group and others suggest another major contributor to pathogenesis: alterations to neurovascular coupling. In Alzheimer’s disease, signaling between neurons and vessels appears to break down, accompanied by defects in vessel responses, cerebral amyloid angiopathy, and structural vascular alterations. However, little is known about the cellular or molecular basis of these changes. In this proposal, we identify a key mechanism responsible for maintaining vessel integrity in the context of aging and Alzheimer’s using the superbly tractable murine retina. We have shown that different retina neuron types exhibit distinct age- and Alzheimer’s disease-related dystrophies, and that dopaminergic neurons are a central target. In parallel, our data now reveal that neural changes are accompanied by distinct vascular dystrophies, with particular disruption to pericytes and their novel nanotube-like processes. Further, using genetic and pharmacological methods we and others have shown that dopamine can directly influence vascular organization and function and signal to pericytes. These data suggest that Alzheimer’s disease alters neuro- vascular coupling via declines in dopamine driven pericyte structure and function. In Aim 1, we determine how Alzheimer’s disease regulates vasculature structure and function, with a particular focus on pericytes. We test the hypothesis that pericyte alterations are accompanied by functional declines in vascular hemodynamics, loss of coupling nanotubes, and locally associated neural decline. In Aim 2, we examine the neural signaling defects causal to vascular structure and functional declines. Our preliminary data suggest that dopaminergic neurons are reduced in Alzheimer’s disease, and that dopamine is required for maintaining vessel integrity. We thus test the idea that declines in dopamine signaling are causal to vasculature dysfunction in Alzheimer’s disease and can be targeted to mitigate vascular pathology. These studies will lead to the identification of molecular pathways that drive neurovascular dysfunction in Alzheimer’s disease that may ultimately be useful for preventing pathogenesis.

项目摘要阿尔茨海默氏病和阿尔茨海默氏病有关的痴呆症的特征是明显改变神经功能和相关的认知下降。尽管对神经元本身的变化很重要，但最近我们小组和其他人的发现提出了发病机理的另一个主要贡献者：改变神经血管耦合。在阿尔茨海默氏病中，神经元和血管之间的信号似乎破裂了向下，伴随血管反应，脑淀粉样血管病和结构血管的缺陷改变。但是，这些变化的细胞或分子基础知之甚少。在这个建议中，我们确定负责在衰老和阿尔茨海默氏症的背景下保持船舶完整性的关键机制使用非常易于处理的鼠视网膜。我们已经表明，不同的视网膜神经元类型暴露了不同年龄和阿尔茨海默氏病与疾病相关的营养不良，多巴胺能神经元是核心靶标。在相关，我们的数据现在表明，神经变化是通过不同的血管营养不良来实现的，对周细胞的特殊破坏及其新颖的纳米管样过程。此外，使用遗传和我们和其他人的药理方法表明，多巴胺可以直接影响血管组织，功能以及向周细胞的信号。这些数据表明，阿尔茨海默氏病改变了神经 - 多巴胺驱动周围结构和功能中通过下降的血管耦合。在AIM 1中，我们确定如何阿尔茨海默氏病调节脉管结构和功能，特别关注周细胞。我们测试在血管血流动力学中的功能下降来实现周细胞改变的假设，偶联纳米管的丧失和局部相关的神经下降。在AIM 2中，我们检查神经信号传导缺陷是血管结构和功能下降的因果关系。我们的初步数据表明多巴胺能在阿尔茨海默氏病中降低了神经元，维持血管完整性所需的多巴胺是必需的。因此，我们测试了多巴胺信号下降的想法是阿尔茨海默氏症血管功能障碍的因果疾病，可以针对减轻血管病理。这些研究将导致确定在阿尔茨海默氏病中驱动神经血管功能障碍的分子途径，最终可能有用用于预防发病机理。