Environmental biosensors in the oligodendrocyte lineage

髓鞘胶质细胞功能是大脑健康的基础，其损害在越来越多的 精神和神经紊乱。研究调控祖细胞向成体转化的基本机制 因此，发育中和成人脑中的髓鞘少突胶质细胞具有更好的 了解调节大脑正常功能的机制，同时告知导致功能障碍的潜在原因， 并为设计新的治疗策略提供了框架。 我们实验室率先提出了少突胶质细胞祖细胞分化的表观遗传调控概念。我们确认了 DNA和组蛋白的变化与发育中髓鞘形成和成人基因表达的抑制有关 重新髓鞘形成，确定了负责的酶，并使用转基因小鼠确定了它们的功能意义， 在神经病理学的背景下描述了它们的特征，并评估了翻译的含义。我们还报告了受损情况 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学调控 多发性硬化症人脑。我们与化学工程师合作开发了能够 逆转一些表观遗传变化。我们还在肠胃之间的串扰方面取得了意想不到的发现。 代谢物、社会体验、机械刺激和髓鞘形成。 概括地说，我们的目标是了解允许化学、新陈代谢和物理 在祖细胞中诱导生物反应并导致髓鞘形成、增殖和 发育中和成人大脑中持续未分化状态的转变。我们的最终目标是 破译驱动祖细胞分化为髓鞘胶质细胞的信号，以便了解 再生策略。在本申请中，我们提出了一种跨学科的方法，其中包括集成 为发现新的信号模式开发新工具和实验方法的几个学科 转导。我们建议使用细胞生物学、生物物理学、先进成像光谱学、纳米技术和超级 分辨率显微镜和新的转基因品系，表观基因组和蛋白质组方法，以解决关键的开放问题 田野。 拟议的研究将开发新的概念，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 实验计划将为开发新的治疗策略奠定基础， 精神障碍，同时促进对大脑发育和髓鞘形成的现有知识。

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.