Environmental biosensors in the oligodendrocyte lineage

髓鞘形成神经胶质功能是大脑健康的基础，并且在越来越多的人中检测到其损伤。 精神和神经疾病。研究调节祖细胞发育的基本机制 因此，在发育和成年大脑中的髓鞘化少突胶质细胞对于更好地 了解调节适当大脑功能的机制，同时告知功能障碍的潜在原因， 并为设计新的治疗策略提供框架。 我们的实验室开创了少突胶质细胞祖细胞分化的表观遗传调控的概念。我们确定 DNA和组蛋白的变化对发育髓鞘形成和成人中基因表达的抑制起作用 髓鞘再生，确定了负责的酶，并使用转基因小鼠定义了它们的功能意义， 在神经病理学的背景下表征它们，并评估其翻译意义。我们还报告说 衰老、抑郁症动物模型和死后少突胶质细胞分化的表观遗传调节 多发性硬化症人类大脑。我们与化学工程师合作，开发出能够 逆转一些表观遗传变化。我们还意外地发现了肠道之间的相互作用 代谢物、社会经验、机械刺激和髓鞘形成。 从广义上讲，我们的目标是了解化学，代谢和物理机制， 环境以诱导祖细胞中的生物反应并导致髓鞘的形成、增殖和分化。 在发育和成人大脑中，未分化状态的持续性转化。我们的最终目标是 破译驱动祖细胞分化为髓鞘形成胶质细胞的信号，以便为设计 再生策略在本申请中，我们提出了一种跨学科的方法，其中包括整合 几个学科开发新的工具和实验方法，发现新的信号形式 转导我们建议使用细胞生物学，生物物理学，先进的成像光谱学，纳米技术和超 分辨率显微镜和新的转基因系，表观基因组学和蛋白质组学方法，以解决关键的开放问题， 外地 这些研究将发展新的概念，并为祖细胞如何解释特定的代谢奠定基础。 信号、机械力、神经元活动来调节大脑功能。我们预计，拟议的 实验计划将为开发几种神经系统疾病的新治疗策略奠定基础， 精神疾病，同时推进目前的知识大脑发育和髓鞘形成。

Myelinating glial function is fundamental for brain health and its impairment is detected in a growing number of psychiatric and neurological disorders. Studying the basic mechanisms regulating the progression of progenitors into myelinating oligodendrocytes in the developing and adult brain therefore has substantial implications for a better understanding of the mechanisms regulating proper brain function, while informing on potential causes for dysfunction, and providing the framework for the design of novel therapeutic strategies. Our lab has pioneered the concept of epigenetic regulation of oligodendrocyte progenitor differentiation. We identified DNA and histone changes responsible for repression of gene expression during developmental myelination and in adult remyelination, identified the responsible enzymes and defined their functional significance using transgenic mice, characterized them in the context of neuropathology and evaluated translational implications. We also reported impaired epigenetic regulation of oligodendrocyte differentiation in aging, in animal models of depression and in post-mortem Multiple Sclerosis human brains. We collaborated with chemical engineers to develop compounds with the ability to reverse some of the epigenetic changes. We also made unanticipated discoveries on the cross-talk between gut metabolites, social experiences, mechanical stimuli and myelination. In broad terms our objective is to understand the mechanisms that allow the chemical, metabolic and physical environment to induce a biological response in progenitor cells and result in the formation of myelin, proliferation and transformation of persistence of an undifferentiated state in the developing and adult brain. Our ultimate goal is to decipher the signals driving the differentiation of progenitors into myelinating glia, in order to inform on the design of regenerative strategies. In this application we propose an interdisciplinary approach, which includes the integration of several disciplines to develop new tools and experimental approaches for the discovery of novel modalities of signal transduction. We propose to use cell biology, biophysics, advanced imaging spectroscopy, nanotechnology and super resolution microscopy and new transgenic lines, epigenomic and proteomic approaches to addresses key open questions in the field. The proposed studies will develop new concepts and set the foundation on how progenitors interpret specific metabolic signals, mechanical forces, neuronal activity to regulate brain function. We expect that the results of the proposed experimental plan will set the stage for the development of novel therapeutic strategies for several neurological and psychiatric disorders, while advancing current knowledge of brain development and myelin formation.