Hemorheological Factors in Cerebral Ischemia

描述（由申请人提供）：该多PI项目将提供卒中和阿尔茨海默病的综合专业知识，以解决广泛流行的脑血管疾病。仔细的神经病理学分析表明，脑显微出血是大脑老化的一个非常常见的特征。目前的项目提案集中在这些出血性的变化，以全面的方式，以确定脑显微出血的解剖学和病理生理学基础，以及制定治疗策略，可以在临床上纳入努力，以减少脑显微出血的后果。 该RO 1于1984年启动，该项目的工作表明大脑具有独特的止血调节能力，这种现象称为“脑特异性止血调节”。最近，我们提出了“混合性脑血管病”的概念，以解决日益认识到的缺血性卒中症状与出血现象并存的患者的临床难题，这些症状在很大程度上是亚临床的。因此，本申请可概念化为结合这两个新概念，即脑特异性止血调节如何介导和调节混合性脑血管疾病。我们的具体目标如下：具体目标1：使用脑淀粉样血管病和衰老模型，在体内证明脑微血管出血的加重、减轻和机制。具体目标二：证明脑淀粉样血管病和衰老介导的体外内皮损伤的微血管完整性改变机制。具体目标3：探讨人脑微出血、血管危险因素、血脑屏障特征和认知功能之间的关系。 这些研究的完成将为保护和维持脑微血管完整性以应对衰老和血管风险的挑战指明方向。这些问题几乎影响了整个人口的预期寿命。这些研究结合了转基因动物模型（可导致脑淀粉样血管病和微出血）、细胞培养研究和人脑尸检样本分析;后者强调了这些研究的临床相关性。该项目的新奇之一是真正的多PI合作努力，结合了中风和阿尔茨海默病的专业知识，有助于提高翻译的重要性。

DESCRIPTION (provided by applicant): This multi-PI project will provide integrated expertise in stroke and Alzheimer's disease to address a cerebrovascular disorder of wide prevalence. Careful neuropathological analyses indicate that cerebral microscopic hemorrhage is an extremely common feature of the aging brain. The current project proposal focuses on these hemorrhagic changes in a comprehensive way, with a goal to define the anatomic and pathophysiological substrate of cerebral microscopic hemorrhage as well as develop therapeutic strategies that can be incorporated clinically in efforts directed to reduce consequences of cerebral microscopic hemorrhage. This RO1 was initiated in 1984 and work from this project has demonstrated that the brain has unique hemostatic regulatory capacities, a phenomenon termed "brain-specific hemostasis regulation." More recently, we have developed the concept of "mixed cerebrovascular disease" to address the increasingly recognized clinical conundrum of patients presenting with ischemic stroke symptoms coexisting with hemorrhagic phenomena that are largely subclinical. The current application may therefore be conceptualized as combining these two novel concepts, ie, how brain specific hemostasis regulation mediates and modulates mixed cerebrovascular disease. Our specific aims are as follows: Specific Aim 1: To demonstrate exacerbation, mitigation, and mechanisms of brain microvascular hemorrhage in vivo, using models of cerebral amyloid angiopathy and aging. Specific Aim 2: To demonstrate microvascular integrity-altering mechanisms of in vitro endothelial injury mediated by cerebral amyloid angiopathy and aging. Specific Aim 3: To demonstrate the relationships between human brain microhemorrhage, vascular risk factors, blood-brain barrier characteristics, and cognitive function. Completion of these studies will point the way toward protection and maintenance of brain microvessel integrity against the challenges of aging and vascular risks. These issues affect virtually the entire population of individuals over the course of the usual lif expectancy. The studies incorporate a transgenic animal model that develops cerebral amyloid angiopathy and microhemorrhages, cell culture studies, and analysis of human brain autopsy samples; the latter emphasizes the clinical relevance of these studies. Part of the novelty of the project is the genuine collaborative multi-PI effort that combines expertise in stroke and Alzheimer's disease, contributing to the high translational significance.