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

项目概要/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？” 脑小血管病是老年人脑出血的主要原因之一 个脑袋CSVD的两种最常见的散发形式是脑淀粉样血管病（CAA）和 小动脉硬化在生活中诊断出CSVD时，潜在的小血管病理学已经 已经发展到了晚期目前还没有针对最后阶段的治疗方法， 血管破裂和出血该提案基于申请人实验室最近的关键观察结果 提示免疫介导的血管重塑和个体血管中β-淀粉样蛋白的减少与 微生物学在CAA这个项目将测试总体假设，即血管周围炎症 导致CAA血管破裂和出血。了解这些 基本的病理生理学机制可以为急需的治疗策略发现新的靶点。 该项目将利用具有神经病理学证实的患者的良好特征的尸检病例 CAA和其他形式的散发性和遗传性CSVD的诊断，以确定共享的途径。的 定量神经病理学在人脑组织样品中的补充使用， 在CAA小鼠模型中的光子显微镜将允许研究导致血管生成的事件序列。 血管壁重塑和出血如果成功，预计该项目的成果将 高影响，因为1）分析针对CSVD发生时存在的疾病阶段 2）炎症途径具有“可用药”的实质可能性（即对候选药物的反应）， 干预），以及3）由于小动脉硬化似乎也需要正常血管壁的逐渐丧失 成分，其次是重塑和血管破裂，有很高的潜力，CAA研究的结果 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.