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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要脑淀粉样血管病（CAA）是由脑动脉上β淀粉样斑块的形成引起的，这会导致平滑肌丧失、血管脆性和颅内出血。 CAA 是一个危险因素痴呆症独立于阿尔茨海默氏病 (AD)，与 AD 类似，没有治疗方法可以逆转或逆转减轻疾病病理。缺乏治疗途径的部分原因是模型系统不足可用于研究疾病并确定治疗策略。虽然转基因小鼠已被改造为尽管发展了 CAA 的某些方面，但没有动物能够完全重现该疾病的表型。而且，大多数动物模型需要一年多的时间才能发展出这种疾病，并且通常由于体内系统的性质，只有可以进行有限数量的测定来测试药物功效并对治疗方案进行分层。因此，要为药物开发提供强大的补充资源，该拟议项目的重点是构建 CAA 体外人类神经血管模型。该模型将建立在我们之前的进展之上将人类诱导多能干细胞 (iPSC) 衍生的神经血管后代纳入三个- 具有代表性功能和适当空间组织的维度组织结构。我们也引入使用预模板低聚物种子控制 CAA 发作和进展的新概念嵌入组织构建体和精确递送的β淀粉样蛋白单体的外源源。目标1 将探索嵌入低聚物和外源单体的浓度，以建立血管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中并根据目标 1 中建立的参数评估 CAA 病理的发生和进展。目标 3 将进行基准测试针对相关小鼠模型和来自 CAA 患者的人体组织观察到的体外病理学。全面的，体外系统是否可以重现 CAA 表型并可重复地模拟疾病的时间进程进展，它将为科学界作为识别和测试的资源提供巨大的价值最终将治疗这种破坏性神经退行性疾病的药物。