iPSC-derived neurovascular tissue model of cerebral amyloiad angiopathy

项目摘要 脑淀粉样血管病(CAA)是由大脑动脉上形成的β淀粉样斑块引起的。 这会导致平滑肌丧失，血管脆弱，以及颅内出血。CAA是一种危险因素 痴呆症独立于阿尔茨海默病(AD)，类似于AD，没有可用的治疗方法来逆转或 减轻疾病病理。这种缺乏治疗途径的部分原因是模型系统不完善。 可用于研究疾病和确定治疗策略。虽然转基因小鼠已经被改造成 发展CAA的某些方面，没有动物完全概括了疾病的表型。此外，大多数动物 模型需要一年多的时间才能发展成这种疾病，而且通常由于体内系统的性质，只有 可以进行有限数量的分析来测试药物疗效和分层治疗方案。因此，要 为药物开发提供强大、互补的资源，这一拟议项目的重点是建立 体外人CAA神经血管模型的建立。该模型将建立在我们以前在 将人类诱导多能干细胞(IPSC)来源的神经血管后代 具有代表性的功能和适当的空间组织的空间组织结构。我们也 介绍一种使用预模板齐聚物种子控制CAA发病和进展的新概念 嵌入到组织结构中，并精确传递β淀粉样单体的外源来源。目标1 将探索浓度的包埋低聚物和外源单体建立血管动力学 无细胞水凝胶中淀粉样蛋白的沉积。目标2将把相关的神经血管细胞类型纳入系统 并根据目标1中建立的参数评估CAA的病理发生和进展。目标3将作为基准 针对相关的小鼠模型和CAA患者的人体组织进行了体外病理观察。总的来说， 如果体外系统能够概括CAA表型并重现疾病的时间进程 进展，它将为科学界提供实质性的价值，作为识别和测试的资源 最终将治疗这种毁灭性的神经退行性疾病的药物。

Project Summary Cerebral amyloid angiopathy (CAA) is caused by the formation of beta amyloid plaques on cerebral arteries, which leads to loss of smooth muscle, vascular fragility, and intracranial hemorrhage. CAA is a risk factor for dementia independent of Alzheimer's Disease (AD), and similar to AD, no treatments are available to reverse or mitigate disease pathology. This lack of therapeutic avenues stems in part from inadequate model systems available to study the disease and identify treatment strategies. While transgenic mice have been engineered to develop certain aspects of CAA, no animal fully recapitulates the disease phenotype. Moreover, most animal models take over a year to develop the disease, and generally owing to the nature of in vivo systems, only a limited number of assays can be conducted to test drug efficacy and stratify treatment regimens. Therefore, to provide a robust, complementary resource for drug development, this proposed project focuses on constructing an in vitro human neurovascular model of CAA. This model will build upon our previous advancements in incorporating human induced pluripotent stem cell (iPSC)-derived neurovascular progenies into three- dimensional tissue constructs with representative function and appropriate spatial organization. We also introduce a novel concept for controlling CAA onset and progression using pre-templated oligomer seeds embedded in the tissue construct and a precisely delivered exogenous source of beta amyloid monomer. Aim 1 will explore concentrations of embedded oligomers and exogenous monomer to establish the kinetics of vascular amyloid deposition in acellular hydrogels. Aim 2 will incorporate relevant neurovascular cell types into the system and assess CAA pathology onset and progression under parameters established in Aim 1. Aim 3 will benchmark the observed in vitro pathology against a relevant mouse model and human tissue from CAA patients. Overall, if the in vitro system can recapitulate CAA phenotypes and reproducibly model the time course of disease progression, it will provide substantial value to the scientific community as a resource for identifying and testing drugs that will ultimately treat this devastating neurodegenerative condition.