Perivascular Inflammation and Vascular Remodeling: A Common Cause of Hemorrhage in Cerebral Small Vessel Diseases?

项目摘要/摘要 标题项目：“血管周围炎症和血管重塑：脑出血的常见原因 小血管疾病？“ 脑小血管病(CSVD)是老年人脑出血的主要原因之一 大脑。CSVD的两种最常见的散发性形式是脑淀粉样血管病(CAA)和 小动脉硬化。在生命中被诊断为CSVD时，潜在的小血管病理已经 已经发展到终末期疾病。目前还没有针对最后几步的治疗方法 血管破裂和出血。这项建议建立在申请人实验室最近的关键观察结果基础上 提示免疫介导的血管重构和单个血管中β-淀粉样蛋白的减少与 CAA内有少量出血。该项目将检验最重要的假设，即血管周围炎症 有助于血管重塑，导致CAA血管破裂和出血。了解这些 基本的病理生理机制可能为急需的治疗策略发现新的靶点。 该项目将利用经过神经病理证实的具有良好特征的尸检病例 诊断CAA和其他形式的散发性和遗传性CSVD，以确定共同的通路。这个 定量神经病理学在人脑组织标本中的互补应用 在CAA小鼠模型中的光子显微镜将有助于研究导致血管形成的事件序列 实时显示室壁重构和出血情况。如果成功，这个项目的结果预计将有 影响大，因为1)分析针对的是CSVD目前的疾病阶段 确诊，2)炎症途径很有可能是可用药的(即对候选对象的反应 干预)，以及3)由于动脉硬化似乎也会导致正常血管壁的逐渐丧失 其次是血管重构和血管破裂，CAA研究的结果有很高的可能性 以推广到其他常见的CSVD。

Project Summary / Abstract Title project: “Perivascular inflammation and vascular remodeling: a common cause of hemorrhage in cerebral small vessel diseases?” Cerebral small vessel disease (CSVD) is a major contributor to intracerebral hemorrhage in the aging human brain. The two most common sporadic forms of CSVD are cerebral amyloid angiopathy (CAA) and arteriolosclerosis. By the time CSVD is diagnosed during life, the underlying small vessel pathology has already advanced to end-stage disease. There are currently no treatments that target the final steps leading up to vessel rupture and hemorrhage. This proposal builds on recent key observations from the applicant’s lab suggesting immune-mediated vascular remodeling and reduced β-amyloid in individual vessels associated with microhemorrhages in CAA. This project will test the overarching hypothesis that perivascular inflammation contributes to vascular remodeling, resulting in vessel rupture and hemorrhage in CAA. Understanding these fundamental pathophysiological mechanisms may uncover novel targets for much needed treatment strategies. This project will leverage well-characterized autopsy cases of patients with a neuropathologically confirmed diagnosis of CAA and other forms of sporadic and hereditary CSVD to determine shared pathways. The complementary use of quantitative neuropathology in human brain tissue samples with longitudinal in vivo two- photon microscopy in mouse models with CAA will allow studying the sequence of events leading up to vessel wall remodeling and hemorrhage in real-time. If successful, the outcomes of this project are expected to have high impact, because 1) the analyses are targeted at the disease stage present at the time CSVD is diagnosed, 2) inflammatory pathways have substantial likelihood to be ‘druggable’ (i.e. response to candidate intervention), and 3) since arteriolosclerosis also seems to entail a gradual loss of normal vessel wall components followed by remodeling and vessel rupture, there is high potential for the results of the CAA study to generalize to the other common CSVD.