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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.项目摘要虽然大多数AD患者是散发性的，但增加AD风险或易感性的几个因素是：发展中的AD相关病理学和认知能力下降。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，损伤淀粉样蛋白依赖性和非依赖性机制已被假定来解释风险诱导 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，以检查与TBI相关的机械损伤之间的联系， AD相关表型的发展仅限于（i）啮齿动物模型，其虽然提供了在理解TBI和AD之间可能的联系方面有价值的信息，不要概括所有和（ii）来自尸体组织样品的神经元细胞，其仅提供最终- 在广泛的离体培养后，疾病的阶段视图和快速松散的疾病相关表型。与通过hiPSC技术，可以从AD患者获得完全分化的细胞类型（例如皮肤细胞并将其重新编程为能够分化为所有成熟细胞类型的细胞类型，成人身体（如皮质的神经细胞）。虽然我们和其他人已经使用AD hiPSC衍生的神经细胞在一个简化和可访问的系统中研究这种疾病，应用基于hiPSC的技术来研究 TBI相关的细胞损伤和AD相关表型的发生之间的联系尚未被证实。办妥了一批为此，我们将利用我们在干细胞生物工程和神经变性方面的集体经验，疾病建模，以开发一个高度可及的体外模型，以阐明潜在的遗传，分子， TBI诱导的细胞损伤的细胞机制导致AD发作和年龄相关的进展。上为了实现这一目标，我们将使用导出的3-D hiPSC验证TBI的机电细胞剪切模型。神经元-星形胶质细胞共培养物。在第二个目标中，随后的表型分析损伤和未损伤的3- 源自非痴呆对照和AD hiPSC的D皮质培养物将揭示（i）HiPSC的直接作用，机械损伤对AD相关毒性刺激敏感性的影响，（ii）潜在的信号通路，受机械损伤和疾病状态独立影响的转录靶标，和（iii）作用机械损伤对AD相关表型的表现或增强的影响。总的来说，确定机械损伤和AD相关表型之间明确关系将具有重要意义，翻译的影响，设计的分子靶向治疗，以治疗许多患者患有 TBI诱导的AD。