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

项目摘要 血管性认知功能障碍（VCI）是由于脑血管疾病引起的任何程度的认知功能改变。 病理学在阿尔茨海默病之后，VCI是痴呆症的第二大原因，约占15-30%。 所有痴呆症病例中。脑小血管疾病（cSVD）占所有卒中的20%，是脑卒中的主要病因。 最常见的病理基础VCI。重要的是，cSVD的发病机制尚未完全了解 这代表了开发该疾病的治疗方法的主要障碍。利用人类的基因模型 我们已经在不同的细胞类型中鉴定出两种潜在的新分子机制， 在老年小鼠中，这可能有助于进行性cSVD。我们的数据表明，cSVD可能代表了一种 具有相似终点的疾病的机制多样性集合以及对多种疾病的研究， 需要疾病模型来理解完整的病理生理特征。我们的跨学科团队 专家将结合独特的遗传资源，血管压力肌造影，膜片钳 电生理学，钙成像，专门的磁共振成像模式和学习， 记忆行为试验，1）使用基因开发和表征cSVD的多种新型遗传模型 2）测试一种潜在疾病修饰剂， 干预和功能分层潜在的不同类别的突变和3）比较相对 不同的神经血管单位细胞类型的贡献，并解决在何种程度上的缺陷是细胞 自主或非自主。我们的长期目标是了解cSVD的异质性 并确定是否有会聚或重叠的途径，可能代表治疗目标， 基于机制的干预。

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.