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

脑小血管疾病和血管性认知障碍新模型的开发和验证

基本信息

批准号：
9894276
负责人：
Myriam Marianne Chaumeil
金额：
$ 50.5万
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：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894276
关键词：
Address Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Ascorbic Acid Behavior Behavioral Biological Assay Biological Markers Blood Vessels Brain CADASIL Calcium Cell Surface Receptors Cerebral small vessel disease Cerebrum Characteristics Clinical Cognitive Cognitive deficits Country Data Dementia Development Disease Disease Pathway Electrophysiology (science)Elements Ensure Etiology Evaluation Experimental Models Female Functional disorder Gene Mutation Genes Genetic Genetic Models Goals Human Image Impaired cognition Intervention Knowledge Lead Learning Lesion Magnetic Resonance Imaging Mediating Memory Meta-Analysis MicroRNAs Microcirculation Microvascular Dysfunction Modeling Molecular Mus Mutant Strains Mice Mutation Myography Outcome Pathogenesis Pathology Pathway interactions Phase Physiological Population Post-Transcriptional Regulation Pre-Clinical Model Preclinical Testing Prevention strategy Process Radiology Specialty Research Stroke Subgroup Syndrome Therapeutic Intervention Validation Vascular Cognitive Impairment Vascular Diseases age related aged arterial tortuosity base behavior test cerebral microbleeds cerebrovascular pathology classical conditioning cognitive change cognitive function cohort comparative design effective intervention genetic resource genome wide association study human disease imaging modality imaging study improved innovation insight male model development mouse model neuropathology novel patch clamp pressure prevent prospective test receptor binding vascular cognitive impairment and dementia white matter

项目摘要

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.

项目概要血管性认知障碍和痴呆（VCID）是指由于以下原因导致的任何程度的认知改变：脑血管病变。 VCID 是仅次于阿尔茨海默病的第二大痴呆症病因，约占所有痴呆症病例的 15-30%。脑小血管疾病 (cSVD) 是一组病理学影响大脑微循环的疾病总共占所有中风的 20%，并且是最常见的 VCID 的常见病理。随着 cSVD 和 VCID 的影响预计将迅速增加美国和其他国家的人口年龄。重要的是，cSVD 的发病机制尚不完全清楚。据了解，这是制定预防和治疗战略的主要障碍。研究该提案中描述的将开发和验证五种基于基因和 CVD 的新型小鼠模型已证明会导致人类疾病的突变。我们组建了一支跨学科团队专家将整合独特的遗传资源、血管压力肌动描记法、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测定，使用以下基因开发和表征 CSVD 的多种新型遗传模型：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再现了人类 cSVD 和 VCID 的重要特征。