A Pluripotent Stem Cell-Based Model to Investigate the Mechanisms of TBI-Induced AD

基于多能干细胞的模型研究 TBI 诱发 AD 的机制

基本信息

批准号：
9903188
负责人：
DAVID A BRAFMAN
金额：
$ 19.02万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903188
关键词：
3-Dimensional Acute Address Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid Amyloid beta-Protein Aneuploidy Animal Model Astrocytes Autopsy Back Biochemical Biological Models Biomechanics Biomedical Engineering Cadaver Cell Death Cell Differentiation process Cell Line Cell membrane Cells Central Nervous System Diseases Coculture Techniques Complex Confounding Factors (Epidemiology)Data Development Disease Disease Progression Disease model Early Onset Familial Alzheimer&apos s Disease Future Generations Genetic Genetic Transcription Human Hypertrophy Impaired cognition Impairment In Vitro Individual Injury Investigation Lead Link Mechanics Methods Modeling Molecular Mutation Neurodegenerative Disorders Neuronal Dysfunction Neurons Onset of illness Pathology Patients Phenotype Pluripotent Stem Cells Predisposition Presenile Alzheimer Dementia Rattus Research Risk Rodent Model Signal Pathway Skin Stimulus System Technology Testing Tissue Sample Traumatic Brain Injury Veins abeta deposition age related astrogliosis base cell cortex cell immortalization cell injury cell type design disorder risk dosage epidemiology study experience experimental study genome-wide human disease human tissue improved in vitro Model in vivo in vivo Model induced pluripotent stem cell injured insight molecular targeted therapies neurotoxic non-demented overexpression stem cell technology stem cells tau Proteins tau mutation translational impact

项目摘要

7. PROJECT SUMMARY ABSTRACT Although the majority of AD patients are sporadic, several factors that increase risk or susceptibility to developing AD-related pathology and cognitive decline have been identified. Specifically, traumatic brain injury (TBI) has been linked to an increased susceptibility to AD and AD-related dementia many years after the initial injury. Amyloid-dependent and -independent mechanisms have been postulated to explain the risk inducing effect of TBI, but the molecular and cellular mechanisms by which TBI increases AD disease risk remain unclear. Current studies to examine the link between the mechanical injury associated with TBI and development of AD-related phenotypes have been limited to (i) rodent models, which while have provided valuable information in understanding possible connections between TBI and AD, do not recapitulate all aspects of the human disease and (ii) neuronal cells from cadaveric tissue samples which only provide an end- stage view of the disease and rapidly loose disease-related phenotypes upon extensive ex vivo culture. With hiPSC technology, it is possible to obtain a fully differentiated cell type (such as a skin cell) from an AD patient and reprogram it back into a cell type that is capable of differentiating into all of the cell types of the mature, adult body (such as neural cells of the cortex). Although we and others have used AD hiPSC-derived neural cells to study this disease in a simplified and accessible system, applying hiPSC-based technologies to study the connection between TBI-related cellular injuries and the onset of AD-related phenotypes has not yet been achieved. To that end, we will use our collective experience in stem cell bioengineering and neurodegenerative disease modeling to develop a highly accessible in vitro model to elucidate potential genetic, molecular, and cellular mechanisms by TBI-induced cellular injuries lead to AD onset and age-related progression. In the first aim of this proposal, we will validate an electro-mechanical cell-shearing model of TBI using 3-D hiPSC derived neuronal-astrocytic co-cultures. In the second aim, subsequent phenotypic analysis of injured and uninjured 3- D cortical cultures derived from non-demented control and AD hiPSCs will reveal the (i) direct effect of the mechanical injury on susceptibility to AD-related toxic stimuli, (ii) potential signaling pathways and transcriptional targets that are independently influenced by mechanical injury and disease status and (iii) effect of mechanical insults on the manifestation or augmentation of AD-related phenotypes. Overall, the ability to identify definitive relationships between mechanical injury and AD-related phenotypes will have a significant translational impact on the design of molecularly targeted therapies to treat the many patients suffering from TBI-induced AD.

7. 项目概要摘要尽管大多数 AD 患者是散发性的，但有几个因素会增加患 AD 的风险或易感性已确定出现 AD 相关病理和认知能力下降。具体来说，创伤性脑损伤 (TBI) 与 AD 和 AD 相关痴呆的易感性增加有关。受伤。淀粉样蛋白依赖性和非淀粉样蛋白依赖性机制已被假设来解释诱发风险的原因 TBI 的影响，但 TBI 增加 AD 疾病风险的分子和细胞机制仍然存在不清楚。目前的研究旨在检验与 TBI 相关的机械损伤与 AD 相关表型的发展仅限于 (i) 啮齿动物模型，这些模型虽然提供了对于理解 TBI 和 AD 之间可能的联系有价值的信息，请勿重述所有内容人类疾病的各个方面和（ii）来自尸体组织样本的神经元细胞仅提供最终结果疾病的阶段视图以及广泛的离体培养后迅速松动的疾病相关表型。和 hiPSC技术，有可能从AD患者身上获得完全分化的细胞类型（如皮肤细胞）并将其重新编程回能够分化为成熟细胞的所有细胞类型的细胞类型，成人身体（例如皮质的神经细胞）。尽管我们和其他人已经使用 AD hiPSC 衍生的神经细胞在一个简化且易于访问的系统中研究这种疾病，应用基于 hiPSC 的技术来研究 TBI 相关细胞损伤与 AD 相关表型发病之间的联系尚未确定实现了。为此，我们将利用我们在干细胞生物工程和神经退行性疾病方面的集体经验疾病建模，开发一种高度可访问的体外模型，以阐明潜在的遗传、分子和 TBI 诱导的细胞损伤导致 AD 发病和年龄相关进展的细胞机制。在第一个为了实现本提案的目标，我们将使用 3-D hiPSC 衍生的 TBI 机电细胞剪切模型进行验证神经元-星形细胞共培养。在第二个目标中，随后对受伤和未受伤的表型进行分析 3- 来自非痴呆对照组和 AD hiPSC 的 D 皮质培养物将揭示 (i) 机械损伤对 AD 相关毒性刺激的易感性，(ii) 潜在的信号传导途径和独立受机械损伤和疾病状态影响的转录靶标以及 (iii) 效应机械损伤对 AD 相关表型的表现或增强的影响。总体而言，能够确定机械损伤和 AD 相关表型之间的明确关系将具有重大意义对分子靶向疗法设计的转化影响，以治疗许多患有这种疾病的患者 TBI 诱发的 AD。