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？

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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小血管病最常见的两种散发形式是脑淀粉样血管病 (CAA) 和当脑小血管病在一生中被诊断出来时，潜在的小血管病变已经发生。目前尚无针对最终阶段的治疗方法。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该项目将检验血管周围炎症的总体假设。有助于血管重塑，导致 CAA 中的血管破裂和出血。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。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如果成功，该项目的成果预计将达到实时墙重塑和出血。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。