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）是脑小血管疾病的常见淀粉样蛋白形式 其特征是纤维状淀粉样蛋白B蛋白（AB）在大脑的血管中积累。 CAA是一个 阿尔茨海默氏病和相关疾病患者的常见血管合并症（ADRD），但也可以 偶发地影响> 50％的个体> 80年。此外，CAA的几种相关家庭形式 由于存在于ABPP基因的AB肽序列中的突变，包括荷兰型（E22Q） 和爱荷华州型（D23N）。 Aβ的脑血管积累会导致血管周神经炎症， 脑梗塞，微孔和在严重的情况下，脑出血（ICH）。因为这些 血管影响，CAA是血管介导的认知障碍和痴呆（VCID）的重要原因。 研究CAA/VCID的发病机理，并开发和测试针对性的治疗干预措施 需要适当的实验动物模型。 迄今为止，对CAA的研究主要集中在使用转基因啮齿动物的情况下。但是，转基因 CAA和ADRD的模型带有几个重大的缺点，包括缓解人工过度的 转化的表达，容易插入对宿主基因组的插入作用，并且容易丧失 转基因表达和随后世代的遗传漂移。转基因的另一个主要缺点 线条是通常发展的病理，通常来自“唯一的表达来源”，通常来自神经元，应有的 驱动转换表达的启动子。但是，神经元AB的“唯一来源”不太可能 CAA在人类中发展。由于CAA中AB的细胞起源的复杂性未在唯一中捕获 Source的转基因模型无法揭示这种疾病的真实发病机理。这个明显的缺点 已经促使人们寻求生成更好的实验动物模型，以更全面地捕获 这种情况的发病机理及其在VCID中的作用。 该探索性建议的总体目标是广泛地表征新型基因编辑的大鼠模型 小容器CAA。这将为CAA领域和ADRD领域提供最先进的动物模型 了解这种病理状况如何准确演变并导致脑血管病理，白色 物质损坏和VCID。该提议的目的是描述一个超级模型，用于研究小型 CAA船只，并为研究社区提供一个更现实和身体上相关的平台 研究致病机制，并能够有效询问新的潜在生物标志物和 CAA的治疗干预措施。