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

血管周围炎症和血管重塑：脑小血管疾病出血的常见原因？

• 批准号: 10861499
• 负责人: Susanne Janneke Van Veluw
• 金额: $ 77.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10861499
• 关键词: Aducanumab; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Area; Arterial Disorder; Arterioloscleroses; Autopsy; Blood Vessels; Brain; Brain hemorrhage; CADASIL; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrum; Clinical; Data Set; Deposition; Development; Diagnosis; Disease; Dutch Type Hereditary Cerebral Amyloid Angiopathy; Event; Excision; Exhibits; Functional disorder; Genetic; Hemorrhage; Human; Hypertension; Immune; Immunohistochemistry; Immunotherapy; Individual; Inflammation; Inflammatory; Inherited; Intervention; Intervention Studies; Investigation; Label; Life; Lobar; Macrophage; Magnetic Resonance Imaging; Mediating; Microglia; Minocycline; Mus; Muscle Proteins; Neurodegenerative Disorders; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Process; Proteomics; Research; Risk; Rupture; Smooth Muscle Myocytes; Sporadic Cerebral Amyloid Angiopathy; Subcortical Infarctions; Subcortical Leukoencephalopathy; Techniques; Testing; Time; Tissue Sample; Vascular Smooth Muscle; Vascular remodeling; aged; arteriole; autosome; brain tissue; comparison group; digital; end stage disease; experimental study; in vivo; insight; mouse model; neuroimaging; neuropathology; novel; novel therapeutics; prevent; response; transcriptomics; treatment strategy; two photon microscopy; vascular inflammation

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.

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（CSVD）是导致老年人脑出血的主要原因 脑。脑小血管病最常见的两种散发形式是脑淀粉样血管病 (CAA) 和 动脉硬化。当脑小血管病在一生中被诊断出来时，潜在的小血管病理学已经 已经进展到终末期疾病。目前还没有针对最终步骤的治疗方法 导致血管破裂、出血。该提案基于申请人实验室最近的重要观察结果 表明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 CAA 中的微出血。该项目将测试血管周围炎症的总体假设 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会发现急需的治疗策略的新靶点。 该项目将利用经过充分表征的神经病理学确诊患者的尸检病例 诊断 CAA 和其他形式的散发性和遗传性 CSVD，以确定共同的途径。这 定量神经病理学在人脑组织样本中的补充使用与纵向体内两个 具有 CAA 的小鼠模型中的光子显微镜将允许研究导致血管形成的事件顺序 实时进行墙壁重塑和出血。如果成功，该项目的成果预计将达到 影响很大，因为 1) 分析针对的是 CSVD 发生时的疾病阶段 诊断，2）炎症途径很可能是“可药用的”（即对候选药物的反应） 干预），3）因为动脉硬化似乎也导致正常血管壁逐渐丧失 成分随后发生重塑和血管破裂，CAA 研究结果的潜力很大 推广到其他常见的 CSVD。