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Mechanisms of Functional Vascular Impairment In Genetic Models of Cerebral Small Vessel Disease

脑小血管疾病遗传模型中功能性血管损伤的机制

基本信息

批准号：
10612694
负责人：
Scott Earley
金额：
$ 15.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612694
关键词：
Address Affect Alleles Alzheimer&apos s Disease Animal Model Astrocytes Basement membrane Behavior Behavioral Behavioral Assay Biological Assay Blood Vessels Calcium Cells Cerebral hemisphere hemorrhage Cerebral small vessel disease Cerebrovascular Disorders Characteristics Chemicals Clinical Cognitive Collagen Type IV Collection Complement Data Defect Dementia Development Disease Disease model Electrophysiology (science)Ensure Extracellular Matrix FDA approved FOXC1 gene Functional disorder Gene Targeting Genes Genetic Genetic Models Health Heterogeneity Homeostasis Human Image Impairment Intervention Investigation Knowledge Lead Learning Lesion Magnetic Resonance Imaging Measures Memory Meta-Analysis Modeling Molecular Molecular Chaperones Mus Mutant Strains Mice Mutation Myography Neurons Outcome Measure Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Pathway interactions Patients Persons Pharmacology Phenotype Phenylbutyrates Physiological Procedures Process Property Radiology Specialty Role Severities Smooth Muscle Myocytes Stratification Stroke Testing Therapeutic Intervention Vascular Cognitive Impairment Vascular Diseases Vascular Endothelial Cell age related aged base cell type cerebral microbleeds cerebrovascular cerebrovascular pathology clinically relevant cognitive change comparative disorder subtype emerging adult genetic resource genome wide association study human disease human model imaging modality mouse model mutant neurovascular unit novel patch clamp pre-clinical pressure preventive intervention recruit response small molecule spatiotemporal therapeutic target therapy development tool vascular contributions white matter

项目摘要

PROJECT SUMMARY Vascular cognitive impairment (VCI) is any level of cognitive alteration that is attributable to cerebrovascular pathologies. After Alzheimer disease, VCI is the second leading cause of dementia and accounts for ~15-30% of all dementia cases. Cerebral small vessel disease (cSVD) accounts for up to 20% of all strokes and is the most common pathology underlying VCI. Importantly, the pathogenesis of cSVD is incompletely understood which represents a major barrier in developing therapies for the disease. Using genetic models of human cSVD we have identified two potentially novel molecular mechanisms in different cell types that only manifest in aged mice and that may contribute to progressive cSVD. Our data suggest that cSVD may represent a mechanistically diverse collection of diseases that share similar endpoints and that investigation of multiple disease models will be required to understand the full pathophysiological profile. Our interdisciplinary team of experts will incorporate unique genetic resources, vascular pressure myography, patch-clamp electrophysiology, calcium imaging, specialized magnetic resonance imaging modalities and learning and memory behavior assays to 1) Develop and characterize multiple novel genetic models of cSVD using genes that contribute to both familial and sporadic disease in humans 2) test a potential disease-modifying intervention and functionally stratify potentially distinct classes of mutations and 3) compare the relative contributions of different neurovascular unit cell types and address the extent to which defects are cell autonomous or non-autonomous. Our long-term objective is to understand the heterogeneity underlying cSVD and determine if there are convergent or overlapping pathways that might represent therapeutic targets for mechanism-based interventions.

项目概要血管性认知障碍（VCI）是由脑血管疾病引起的任何程度的认知改变病理学。 VCI 是继阿尔茨海默病之后导致痴呆的第二大原因，约占 15-30% 所有痴呆症病例中。脑小血管病 (cSVD) 占所有中风的 20%，是 VCI 的最常见病理。重要的是，cSVD 的发病机制尚不完全清楚这是开发该疾病疗法的主要障碍。使用人类遗传模型 cSVD 我们在不同细胞类型中发现了两种潜在的新颖分子机制，这些机制仅表现出来在老年小鼠中，这可能会导致进行性 SVD。我们的数据表明，cSVD 可能代表具有相似终点的机械上不同的疾病集合以及对多种疾病的调查需要疾病模型来了解完整的病理生理学特征。我们的跨学科团队专家将结合独特的遗传资源、血管压力肌电图、膜片钳电生理学、钙成像、专门的磁共振成像模式以及学习和记忆行为分析 1) 使用基因开发和表征多个新型 CSVD 遗传模型导致人类家族性和散发性疾病的因素 2) 测试潜在的疾病缓解方法干预并对潜在不同类别的突变进行功能分层，3）比较相对不同神经血管单位细胞类型的贡献，并解决细胞缺陷的程度自主或非自主。我们的长期目标是了解 cSVD 背后的异质性并确定是否存在可能代表治疗靶点的汇聚或重叠途径基于机制的干预措施。