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

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

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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.

项目摘要 /摘要标题项目：“血管周围注射和血管重塑：大脑出血的常见原因小血管疾病？” 脑小血管疾病（CSVD）是衰老人衰老的脑内出血的主要因素脑。 CSVD的两种最常见的形式是脑淀粉样血管病（CAA）和动脉粥样硬化。到CSVD在生命中被诊断出来时，潜在的小血管病理已经已经患上了终点疾病。目前尚无针对最终步骤的治疗方法船舶破裂和出血。该提案以申请人实验室的最新关键观察为基础提示免疫介导的血管重塑，并减少与 CAA中的微视角。该项目将测试周围注射的总体假设导致血管重塑，导致CAA的血管破裂和出血。了解这些基本的病理生理机制可能会发现急需治疗策略的新目标。该项目将利用神经病理学确认的患者的训练术病例诊断CAA和其他形式的零星和遗传性CSVD，以确定共享途径。这在人类脑组织样品中完全使用定量神经病理学具有CAA的小鼠模型中的光子显微镜将允许研究导致血管的事件序列实时重塑和出血。如果成功，则预计该项目的结果将有高影响力，因为1）分析是针对CSVD当时存在的疾病阶段被诊断为2）炎症途径很有可能是“可药的”（即对候选人的反应干预）和3），因为动脉硬化似乎也导致正常血管壁的损失组件随后进行了重塑和血管破裂，CAA研究的结果很高概括到其他常见的CSVD。