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。项目摘要摘要尽管大多数AD患者都是零星的，但增加了一些因素已经确定了发展与广告相关的病理和认知下降。具体而言，脑损伤（TBI）已与对AD的易感性增加了，并且在初始多年后多年受伤。已经假定了淀粉样蛋白依赖性和非依赖性机制来解释诱导风险 TBI的影响，但是TBI增加AD疾病风险的分子和细胞机制仍然存在不清楚。目前的研究检查与TBI相关的机械损伤与与广告相关的表型的开发仅限于（i）啮齿动物模型，虽然已提供了解TBI和AD之间可能联系的宝贵信息，不要概括所有人类疾病的各个方面和（ii）来自尸体组织样品的神经元细胞，仅提供末端在广泛的离体培养物上，该疾病的阶段视图和与疾病相关的表型迅速松散。和 HIPSC技术，可以从广告患者那里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区分成熟的所有细胞类型的单元格类型成人身体（例如皮质的神经细胞）。尽管我们和其他人使用了AD HIPSC衍生的神经细胞在简化且可访问的系统中研究该疾病，应用基于HIPSC的技术来研究与TBI相关的细胞损伤与广告相关表型的发作之间的联系尚未成就了。为此，我们将在干细胞生物工程和神经退行性中使用我们的集体经验疾病建模以开发高度可访问的体外模型，以阐明潜在的遗传，分子和 TBI诱导的细胞损伤的细胞机制导致AD发作和与年龄有关的进展。在第一个该提案的目的，我们将使用3-D HIPSC衍生神经元群体共培养。在第二个目标中，随后对受伤和未受伤的表型分析3- d从非痴呆控制和AD HIPSC中得出的皮质培养物将揭示（i）直接影响机械损伤对广告相关毒性刺激的易感性，（ii）潜在信号通路和受到机械损伤和疾病状态独立影响的转录靶标，以及（iii）效应对广告相关表型的表现或增强机械侮辱。总体而言，能力确定机械损伤和与AD相关的表型之间的确定关系将具有显着翻译对分子靶向疗法设计的影响，以治疗许多患者 TBI引起的广告。