Novel Gene-Edited Rat Model for Development of CAA

用于开发 CAA 的新型基因编辑大鼠模型

• 批准号: 10574070
• 负责人: William E. Van Nostrand
• 金额: $ 45.26万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574070
• 关键词: Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Animal Model; Arteries; Behavioral; Biochemical; Blood Vessels; Brain; Brain Pathology; Cerebral Amyloid Angiopathy; Cerebral Infarction; Cerebral cortex; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrovascular system; Cognitive; Communities; Dementia; Disease; Elderly; Endothelial Cells; Experimental Animal Model; Generations; Genes; Genetic Drift; Genome; Glare; Goals; Human; Impaired cognition; Individual; Iowa; Knock-in; Knock-out; Magnetic Resonance Imaging; Mediating; Meninges; Modeling; Mutation; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pericytes; Physiological; Production; Rattus; Research; Research Personnel; Resolution; Rodent; Rodent Model; Role; Site; Smooth Muscle Myocytes; Source; Study models; Testing; Therapeutic Intervention; Transgenes; Transgenic Model; Transgenic Organisms; abeta accumulation; arteriole; cell type; cerebral capillary; cerebral microvasculature; cerebrovascular; cognitive function; comorbidity; experimental study; model development; mutant; neuroimaging; neuroinflammation; novel; overexpression; potential biomarker; pre-clinical; promoter; protein aminoacid sequence; targeted treatment; transgene expression; vascular cognitive impairment and dementia; white matter damage

Cerebral amyloid angiopathy (CAA) is a common amyloidal form of cerebral small vessel disease that is characterized by the accumulation of fibrillar amyloid b-protein (Ab) in blood vessels of the brain. CAA is a common vascular comorbidity in patients with Alzheimer’s disease and related disorders (ADRD) but also can occur sporadically affecting >50% of individuals >80 years. In addition, several related familial forms of CAA result from mutations that reside within the Ab peptide sequence of AbPP gene including Dutch-type (E22Q) and Iowa-type (D23N). Cerebral vascular accumulation of Aβ can result in perivascular neuroinflammation, cerebral infarction, microbleeds, and in severe cases, intracerebral hemorrhages (ICH). Because of these vascular impacts, CAA is a significant cause of vascular-mediated cognitive impairment and dementia (VCID). To investigate the pathogenesis of CAA/VCID and to develop and test targeted therapeutic interventions for this condition appropriate experimental animal models are needed. To date, studies on CAA have largely centered around the use of transgenic rodents. However, transgenic models of CAA and ADRDs come with several significant shortcomings including reliance on artificial over- expression of the transgene, prone to insertional effects on the host genome and susceptible to loss of transgene expression and genetic drift in subsequent generations. Another major shortcoming of transgenic lines is that pathology that develops typically is from a ‘sole source’ of expression, typically from neurons, due to the promoters that drive transgene expression. However, a ‘sole source’ of neuronal Ab is unlikely how the CAA develops in humans. Since the complexity of the cellular origins of Ab in CAA are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this disorder. This glaring shortcoming has prompted the quest to generate yet a better experimental animal model for CAA to more fully capture the pathogenesis of this condition and its role in VCID. The overall goal of this exploratory proposal is to extensively characterize a novel gene-edited rat model for small vessel CAA. This will provide a state-of-the-art animal model to the field of CAA and ADRD to more fully understand how this pathological condition accurately evolves and leads to cerebral vascular pathology, white matter damage, and VCID. The aim of this proposal is to describe a superior model for the study of small vessel CAA and provide to the research community a more realistic and physiologically relevant platform to investigate pathogenic mechanisms and to be able to effectively interrogate new potential biomarkers and therapeutic interventions for CAA.

脑淀粉样血管病（CAA）是一种常见的淀粉样脑小血管疾病