Hemorheological Factors in Cerebral Ischemia

项目总结/摘要 该项目（始于1984年）继续其长期目标，通过小说， 机械研究。我们的主要兴趣是脑微出血， 脑微出血和微血管性脑疾病的主要出血成分。拟议 该项目将利用脑微出血的新动物模型， 解决红细胞（RBC）-内皮相互作用的微出血和尖端分析技术。 我们的目标是确定广泛影响脑微出血发展的机制， 那些更具体地与微出血的个体血管风险因素相关的研究， 一支独特的研究人员团队，拥有中风神经病学、血管神经生物学、肾脏病学的专业知识， 生物工程和生物统计学，所有这些都与动物和细胞培养研究有关。 我们具体提出以下目标： 具体目标1：确定脑微出血的机制。 具体目标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RBC穿过脑微血管的跨细胞机制 内皮细胞 所提出的研究被设计为一系列协同实验，这些实验将体内和体内的联合收割机结合起来。 体外研究提供新的见解微血管脑疾病。我们将结合以下研究， 微血管生理学和神经病理学，以确定脑微出血的血管来源， 描述了RBC和脑微血管内皮细胞之间的相互作用， 建立脑微出血。该项目是我们在大部分时间内完成的工作的直接延伸 最近的资助期间，这项赠款，并纳入新的动物模型的脑微出血和新的 描述微出血发病机制的概念模型。我们的体内研究将解决的机制， 衰老、高血压和慢性肾脏疾病在微出血发展中的作用，沿着小胶质细胞的作用 和基质金属蛋白酶-9。 该项目直接解决了高度流行的出血性微血管疾病的问题， 大脑我们和其他人的工作表明，微出血性贫血几乎无处不在， 老化的人脑中的变化我们的多学科调查团队有独特的能力 项目完成，直接测试我们的微出血概念模型，期望强大的见解 将有助于改变大脑微血管疾病的管理，沿着 阿尔茨海默氏病是老年神经系统疾病的最常见原因。

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.