Environmental biosensors in the oligodendrocyte lineage

少突胶质细胞谱系中的环境生物传感器

基本信息

批准号：
10397521
负责人：
Patrizia Casaccia
金额：
$ 115.1万
依托单位：
ADVANCED SCIENCE RESEARCH CENTER
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：
2019-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397521
关键词：
Address Adult Aging Animal Model Automobile Driving Autopsy Biological Biology Biophysics Biosensor Brain Cell Lineage Cellular biology Chemical Engineering Chemicals DNA Detection Development Discipline Enzymes Epigenetic Process Foundations Functional disorder Gene Expression Goals Histones Human Impairment Knowledge Mental disorders Metabolic Microscopy Modality Multiple Sclerosis Myelin Nanotechnology Neuroglia Neurologic Neurons Oligodendroglia Physical environment Process Proteomics Regulation Reporting Resolution Signal Transduction Social Environment Stimulus Transgenic Mice Transgenic Organisms Undifferentiated brain health depression model design epigenetic regulation epigenomics experience gene repression interdisciplinary approach interest mechanical force mechanical stimulus myelination nervous system disorder neuropathology novel novel therapeutic intervention oligodendrocyte lineage oligodendrocyte progenitor progenitor regenerative regenerative approach remyelination response social spectroscopic imaging stem cells tool

项目摘要

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.

髓鞘神经胶质功能对于大脑健康至关重要，越来越多的人发现其受损精神和神经系统疾病。研究调节祖细胞进展的基本机制因此，发育中和成年大脑中的髓鞘少突胶质细胞对于更好地发挥作用具有重大意义。了解调节正常大脑功能的机制，同时了解功能障碍的潜在原因，并为设计新颖的治疗策略提供框架。我们的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的概念。我们确定了 DNA 和组蛋白的变化导致髓鞘发育过程中和成人中基因表达的抑制髓鞘再生，使用转基因小鼠鉴定了负责的酶并定义了它们的功能意义，在神经病理学背景下对它们进行了表征并评估了转化意义。我们还报告了受损情况衰老、抑郁动物模型和死后少突胶质细胞分化的表观遗传调控多发性硬化症人脑。我们与化学工程师合作开发能够逆转一些表观遗传变化。我们还在肠道之间的串扰方面取得了意想不到的发现代谢物、社会经历、机械刺激和髓鞘形成。从广义上讲，我们的目标是了解化学、代谢和物理作用的机制环境诱导祖细胞发生生物反应，导致髓磷脂的形成、增殖和发育中和成人大脑中未分化状态持续性的转变。我们的最终目标是破译驱动祖细胞分化为髓鞘神经胶质细胞的信号，以便为设计提供信息再生策略。在此应用中，我们提出了一种跨学科方法，其中包括整合多个学科开发新工具和实验方法来发现新的信号模式转导。我们建议利用细胞生物学、生物物理学、先进成像光谱学、纳米技术和超级技术分辨率显微镜和新的转基因系、表观基因组和蛋白质组方法来解决关键的开放性问题领域。拟议的研究将发展新概念并为祖细胞如何解释特定代谢奠定基础信号、机械力、神经元活动来调节大脑功能。我们预计拟议的结果实验计划将为多种神经系统和疾病的新治疗策略的开发奠定基础精神疾病，同时推进当前对大脑发育和髓磷脂形成的了解。