Development and validation of novel models for cerebral small vessel disease and vascular cognitive impairment

项目摘要 血管性认知障碍和痴呆（VCID）是可归因于以下因素的任何水平的认知改变： 脑血管病VCID是仅次于阿尔茨海默病的第二大痴呆症病因， 占所有痴呆病例的15-30%。脑小血管疾病（cSVD）是一组病理学 影响大脑的微循环，这些微循环总共占所有中风的20%， VCID背后的共同病理cSVD和VCID的影响预计将迅速增加， 美国和其他国家的人口老龄化。重要的是，cSVD的发病机制是不完全的， 这是制定预防和治疗战略的一个主要障碍。研究 该提案中描述的将开发和验证五种基于基因的cSVD新型小鼠模型， 这些突变被证明会导致人类疾病。我们组建了一个跨学科的团队 的专家，将整合独特的遗传资源，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和学习， 记忆行为测定，以开发和表征cSVD的多种新的遗传模型， 会导致人类疾病我们的长期目标是开发和使用遗传模型， 忠实地概括了人cSVD和VCID的重要特征。

PROJECT SUMMARY Vascular cognitive impairment and dementia (VCID) is any level of cognitive alteration that is attributable to cerebrovascular pathologies. VCID is second only to Alzheimer's disease as a cause of dementia and accounts for ~15-30% of all dementia cases. Cerebral small vessel diseases (cSVDs) are group of pathologies afflicting the microcirculation of the brain that collectively account for up to 20% of all strokes and is the most common pathology underlying VCID. The impact of cSVD and VCID is expected to increase rapidly as the population of the US and other countries ages. Importantly, the pathogeneses of cSVDs are incompletely understood which represents a major barrier in developing strategies for prevention and treatment. Research described in this proposal will develop and validate five novel mouse models of cSVD based on genes and mutations that are demonstrated to contribute to human disease. We have assembled an interdisciplinary team of experts that will integrate unique genetic resources, vascular pressure myography, patch-clamp electrophysiology, calcium imaging, specialized magnetic resonance imaging modalities and learning and memory behavior assays to develop and characterize multiple novel genetic models of cSVD using genes that contribute to disease in humans. Our long-term objective is to develop and employ genetic models that faithfully recapitulate important hallmarks of human cSVD and VCID.