Develop age-relevant glial cellular models using human directly reprogrammed cells

项目摘要 大脑老化的特点是认知能力、学习和记忆能力下降。的确切机制 大脑老化的可能性仍然很小。因为衰老是主要衰弱性神经退行性疾病的最大风险因素 在包括阿尔茨海默病（AD）在内的多种疾病中，重要的是要揭示大脑衰老的潜在机制， 目的是为年龄相关的神经退行性疾病开发有效的治疗方法。 AD是最常见的神经退行性疾病，是导致残疾和死亡的主要原因。然而，在这方面， AD发病机制的确切机制仍有待阐明。虽然许多转基因 已经产生了用于AD研究的小鼠模型，并且这些模型对于我们理解AD是重要的。 疾病的病理基础，人们越来越认识到，有显着的物种差异 小鼠和人类神经细胞之间的差异。因此，迫切需要建立人类疾病模型 平台，以补充AD研究的动物模型研究。 直接重编程是一种细胞重编程技术，其允许直接转化一种类型的细胞， 体细胞，如成纤维细胞，转化为另一种类型的体细胞，如神经元。已经显示 直接重编程使得能够产生具有细胞老化的关键要素的人类神经元。 因此，直接重编程的细胞可以为我们提供一个人类细胞平台来模拟大脑衰老， 与年龄相关的迟发性疾病，如迟发性AD（LOAD）。 本研究的目的是利用直接免疫荧光技术建立人年龄相关的神经胶质细胞模型。 重编程技术，以概括大脑老化中与年龄相关的表型， 神经退行性变和发现新的潜在机制。越来越多的证据表明星形胶质细胞 在大脑健康和神经退行性疾病的发病机制中发挥重要作用。因此，我们建议 利用老年成纤维细胞直接重编程星形胶质细胞建立脑老化和AD的细胞模型 受试者和LOAD患者以及星形胶质细胞与其他脑细胞类型，包括小胶质细胞， 少突胶质细胞和神经元。我们假设细胞衰老调节星形胶质细胞功能和细胞-细胞关系。 相互作用以调节脑老化表型和LOAD病理。因此，我们建议如下： 具体目的：目的1：通过直接重编程产生年龄相关的星形胶质细胞，并评估如何 细胞老化调节星形胶质细胞功能。目的2：确定星形胶质细胞是否以及如何衰老 调节神经炎症和神经元表型。目的3：确定星形胶质细胞是否以及如何 细胞老化调节OPC特性和髓鞘形成。拟议的研究可能有助于确定 神经胶质细胞衰老在脑功能老化过程中的作用，并揭示其内在机制， 可能导致新的策略的发展，以保持大脑健康和降低AD的风险。知识 从这项研究中获得的信息可以帮助我们设计新的AD治疗策略。

Project Summary Brain aging is characterized by reduced cognitive capacities, learning and memory. The exact mechanisms of brain aging remain elusive. Because aging is the greatest risk factor for major debilitating neurodegenerative disorders, including Alzheimer's disease (AD), it is important to uncover mechanisms underlying brain aging in order to develop effective therapies for age-related neurodegenerative diseases. AD is the most common neurodegenerative disorder and a leading cause of disability and death. However, the precise mechanisms underlying AD pathogenesis remains to be elucidated. Although many transgenic mouse models have been generated for AD research and these models are important for our understanding of the pathological basis of the disease, it is increasingly recognized that there are significant species differences between mouse and human neural cells. Therefore, there is an urgent need to establish human disease modeling platforms to complement studies in animal models for AD research. Direct reprogramming is a cellular reprogramming technology, which allows direct conversion of one type of somatic cells, such as fibroblasts, into another type of somatic cells, such as neurons. It has been shown that direct reprogramming enables generation of human neurons that possess key elements of cellular aging. Therefore, directly reprogrammed cells could provide a human cellular platform for us to model brain aging and age-related late-onset diseases, such as late-onset AD (LOAD). The objective of this proposal is to develop human age-relevant glial cellular models using direct reprogramming technology, in order to recapitulate age-associated phenotypes in brain aging and neurodegeneration and uncover novel underlying mechanisms. Increasing evidence suggests that astrocytes play important roles in brain health and pathogenesis of neurodegenerative diseases. Therefore, we propose to establish cellular models for brain aging and AD using astrocytes directly reprogrammed from fibroblasts of aged subjects and LOAD patients and co-cultures of astrocytes with other brain cell types, including microglia, oligodendrocytes, and neurons. We hypothesize that cellular aging regulates astrocyte function and cell-cell interactions to modulate brain aging phenotypes and LOAD pathologies. Accordingly, we propose the following Specific Aims:Aim 1: To generate age-associated astrocytes through direct reprogramming and evaluate how cellular aging regulates astrocytic functions. Aim 2: To determine whether and how astrocytic cellular aging modulates neuroinflammation and neuronal phenotypes. Aim 3: To determine whether and how astrocytic cellular aging regulates OPC properties and myelination. The proposed studies will likely help to define roles of glial cellular aging in brain functional deterioration during aging and uncover the underlying mechanisms, which could lead to the development of novel strategies to maintain brain health and reduce risk for AD. The knowledge gained from this study could help us to design novel therapeutic strategies for AD.