iPSC-derived neurovascular tissue model of cerebral amyloiad angiopathy

iPSC 衍生的脑淀粉样血管病神经血管组织模型

• 批准号: 10044329
• 负责人: Ethan Lippmann
• 金额: $ 83.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044329
• 关键词: 3-Dimensional; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Model; Animals; Architecture; Benchmarking; Biological Assay; Biological Models; Biomedical Engineering; Blood Vessels; Cell physiology; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrovascular system; Cerebrum; Communities; Complement; Data; Dementia; Deposition; Disease; Disease Progression; Disease model; Drug Screening; Engineering; Familial Cerebral Amyloid Angiopathy; Goals; Harvest; Hemorrhage; Human; Hydrogels; Image; Impaired cognition; In Vitro; Intracranial Hemorrhages; Kinetics; Location; Modeling; Monitor; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathology; Patients; Perfusion; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Process; Reproducibility; Resources; Risk Factors; Scientist; Seeds; Senile Plaques; Smooth Muscle; Smooth Muscle Myocytes; Source; System; Techniques; Therapeutic; Time; Tissue Model; Tissue Sample; Tissues; Transgenic Mice; Treatment Protocols; Vascular Dementia; Vascular Smooth Muscle; Work; abeta oligomer; base; beta amyloid pathology; brain parenchyma; burden of illness; cell type; cerebral artery; dementia risk; disease phenotype; drug development; drug discovery; drug efficacy; drug resource; drug testing; genetic variant; human model; human tissue; in vitro Model; in vivo; induced pluripotent stem cell; lifestyle intervention; monomer; mouse model; neurovascular; novel; older patient; overexpression; prevent; quantitative imaging; stem; stem cells; treatment strategy

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.

项目摘要 脑淀粉样血管病（CAA）是由脑动脉上β淀粉样斑块的形成引起的， 导致平滑肌丧失、血管脆性和颅内出血。CAA是一个危险因素， 痴呆独立于阿尔茨海默病（AD），并且类似于AD，没有治疗可用于逆转或 减轻疾病病理学。这种治疗途径的缺乏部分源于不适当的模型系统 研究疾病并确定治疗策略。虽然转基因小鼠已经被改造成 虽然没有动物发展CAA的某些方面，但没有动物完全重现疾病表型。此外，大多数动物 模型需要一年多的时间来发展疾病，并且通常由于体内系统的性质， 可以进行有限数量的测定来测试药物功效和分层治疗方案。因此 为药物开发提供强大的补充资源，该拟议项目的重点是建设 CAA的体外人神经血管模型。该模型将建立在我们以前的进步， 将人诱导多能干细胞（iPSC）衍生的神经血管后代并入三个- 具有代表性功能和适当空间组织的三维组织构建体。我们也 介绍了使用预模板化寡聚物种子控制CAA发作和进展的新概念 嵌入组织构建体中，并精确递送β淀粉样蛋白单体的外源性来源。要求1 将探索嵌入的寡聚体和外源性单体的浓度，以建立血管内皮细胞的动力学。 无细胞水凝胶中的淀粉样蛋白沉积。目标2将相关的神经血管细胞类型纳入系统 并在目标1中建立的参数下评估CAA病理学发作和进展。目标3将基准 在相关小鼠模型和CAA患者的人体组织中观察到的体外病理学。总的来说， 如果体外系统可以重现CAA表型并可再现地模拟疾病的时间进程， 它将为科学界提供实质性价值，作为识别和测试的资源。 最终能治疗这种毁灭性神经退行性疾病的药物。