Novel Gene-Edited Rat Model for Development of CAA

脑淀粉样血管病(CAA)是一种常见的淀粉样脑血管小血管疾病 以脑血管中纤维状淀粉样蛋白b(Ab)的积聚为特征。CAA是一种 阿尔茨海默病及相关疾病(ADRD)患者常见的血管共病，但也可以 零星发生，影响&>50%的人&>80岁。此外，CAA的几种相关家族性形式 由ABPP基因抗原肽序列中的突变所致，包括荷兰型(E22Q) 和爱荷华型(D23N)。脑血管内Aβ积聚可导致血管周围神经炎， 脑梗塞、微出血，严重者为脑出血(ICH)。正因为如此 血管撞击，CAA是血管介导性认知障碍和痴呆(VCID)的重要原因。 探讨CAA/VCID的发病机制，并开发和测试靶向治疗干预措施 在这种情况下，需要合适的实验动物模型。 到目前为止，对CAA的研究主要集中在转基因啮齿动物的使用上。然而，转基因 CAA和ADRD模型有几个重大缺陷，包括对人为过度依赖 转基因的表达，容易对宿主基因组产生插入效应，并容易丢失 转基因表达和后代的遗传漂移。转基因的另一个主要缺点 LINES是一种典型的病理现象，它是由一种“唯一来源”的表达形成的，通常是来自神经元。 到驱动转基因表达的启动子。然而，神经元抗体的“唯一来源”不太可能是 慢性再生障碍性贫血在人类体内发生。由于CAA中抗体细胞起源的复杂性不是在Sole中捕捉到的 来源的转基因模型他们未能揭示这种疾病的真正发病机制。这一明显的缺点 促使人们寻求为CAA建立更好的实验动物模型，以更全面地捕捉 这种情况的发病机制及其在VCID中的作用。 这一探索性提案的总体目标是广泛地表征一种新的基因编辑的大鼠模型 小型船舶CAA。这将为CAA和ADRD领域提供一个更全面的最先进的动物模型 了解这种病理状态如何准确演变并导致脑血管病理，怀特 物质伤害和VCID。这项建议的目的是描述一个更好的模型来研究Small 血管CAA，并为研究界提供一个更现实和生理上相关的平台 研究致病机制，并能够有效地询问新的潜在生物标志物和 CAA的治疗干预。

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.