Hemorheological Factors in Cerebral Ischemia

项目摘要/摘要 该项目(始于1984年)继续其长期目标，即通过小说提高对中风的理解 机械式的调查。我们的主要兴趣是脑微出血，这是脑出血的病理基础 脑微出血和微血管脑病的主要出血成分。建议数 该项目将利用脑微出血的新动物模型、新的细胞培养模型和 针对红细胞(RBC)-内皮相互作用的微量出血，以及尖端分析技术。 我们的目标是确定广泛影响脑微出血发展的机制以及 那些更具体地与微出血的单个血管风险因素有关的因素，项目调查人员是 一组独特的研究人员，他们在中风神经学、血管神经生物学、肾脏病、 生物工程和生物统计学，都具有与动物和细胞培养研究相关的能力。 我们具体提出以下目标： 具体目的1：探讨脑微出血的体内发病机制。 特定目标2：描述红细胞通过脑微血管的细胞旁机制 体外培养内皮细胞。 具体目标3：描述红细胞通过脑微血管的跨细胞机制 内皮细胞。 拟议的研究被设计为一系列结合体内和体内的协同实验。 体外研究，为微血管脑部疾病提供新的见解。我们将使用以下研究的组合 微血管生理学和神经病理学以确定脑微出血的血管来源并 描绘出红细胞和脑微血管内皮细胞之间的相互作用 建立脑微出血模型。该项目是我们在大多数时间内完成的工作的直接延伸 最近的资助期，并纳入了新的脑微出血动物模型和新的 描述微出血发病机制的概念模型。我们的体内研究将解决 衰老、高血压和慢性肾脏疾病在小出血发生中的作用以及小胶质细胞的作用 和基质金属蛋白酶-9。 该项目直接解决了出血性微血管疾病的高度流行问题。 大脑。我们的研究和其他人的研究表明，微出血几乎无处不在。 老化的人脑的变化。我们的多学科调查团队是独一无二的有能力 项目完成，直接测试我们的微出血概念模型，期望强大的洞察力 将有助于改变脑部微血管疾病的管理， 阿尔茨海默病是导致神经衰老的最常见原因。

Project Summary/Abstract This project (begun in 1984) continues its long-term goal to enhance understanding of stroke by novel mechanistic investigations. Our principal interest is cerebral microhemorrhage, the pathological substrate of cerebral microbleeds and the major hemorrhagic component of microvascular cerebral disease. The proposed project will utilize a combination of novel animal models of cerebral microbleeds, new cell culture models of microbleeds that address red blood cell (RBC)-endothelial interactions, and cutting edge analytic techniques. Our objective is to identify mechanisms that broadly impact development of cerebral microbleeds as well as those more specifically related to individual vascular risk factors for microbleeds, The project investigators are a unique group of investigators with expertise in stroke neurology, vascular neurobiology, nephrology, bioengineering, and biostatistics, all with capabilities relevant to animal and cell culture studies. We specifically propose the following aims: Specific Aim 1: To determine mechanisms of cerebral microhemorrhage in vivo. Specific Aim 2: To delineate paracellular mechanisms of RBC passage across brain microvascular endothelium in vitro. Specific Aim 3: To delineate transcellular mechanisms of RBC passage across brain microvascular endothelium. The proposed studies are designed as a series of synergistic experiments that combine in vivo and in vitro studies to provide novel insights into microvascular brain disease. We will use a combination of studies of microvascular physiology and neuropathology to identify the vascular source of cerebral microbleeds and to delineate those interactions between RBC and brain microvascular endothelium that immediately precede establishment of cerebral microbleeds. The project is a direct extension of work we completed during the most recent funding period of this grant and incorporate new animal models of cerebral microbleeds and novel conceptual models describing microbleed pathogenesis. Our in vivo studies will address mechanisms of aging, hypertension, and chronic kidney disease in microbleed development, along with the roles of microglia and matrix metalloproteinase-9. This project directly addresses the highly prevalent problem of hemorrhagic microvascular disease of the brain. Our work and that of others have shown the near-ubiquitous presence of microhemorrhagic changes in aging human brain. Our multi-disciplinary team of investigators are uniquely capable of taking this project to completion, directly testing our microbleed conceptual models in the expectation that robust insights will emerge helping to transform the management of microvascular disorders of the brain which, along with Alzheimer’s disease, represents the most common cause of neurological morbidity of aging.