Hemorheological Factors in Cerebral Ischemia

描述（由申请人提供）：这个多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，脑出血是衰老大脑的一个极其常见的特征。目前的项目提案以全面的方式关注这些出血变化，目的是确定脑显微出血的解剖和病理生理基础，并制定可用于临床的治疗策略，以减少脑显微出血的后果。这个RO1始于1984年，该项目的工作表明，大脑具有独特的止血调节能力，这种现象被称为“脑特异性止血调节”。最近，我们提出了“混合性脑血管疾病”的概念，以解决越来越多的临床难题，即出现缺血性卒中症状的患者同时出现亚临床的出血现象。因此，目前的应用可能被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。我们的具体目的如下：具体目的1：利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剧、缓解和机制。特异性目的2：研究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。具体目的3：证明人脑微出血、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大脑微血管的完整性以对抗衰老和血管风险的挑战指明方向。这些问题实际上影响到整个人群的正常预期寿命。这些研究包括一种产生脑淀粉样血管病和微出血的转基因动物模型、细胞培养研究和人脑尸检样本分析；后者强调这些研究的临床相关性。该项目的部分新颖之处在于真正的多pi合作努力，结合了中风和阿尔茨海默病的专业知识，有助于提高转化意义。

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.