Extracellular matrix regulation of myelination

髓鞘形成对大脑的发育和功能是必不可少的，但控制脑髓鞘形成的精确机制 髓鞘少突胶质细胞的发育尚不清楚。在脱髓鞘疾病中如多发性 硬化症，髓鞘的丧失也被认为是导致神经退化的原因之一。多发性骨髓瘤髓鞘异常 自闭症、精神分裂症和阿尔茨海默病的病因不明。要监管的候选人 髓鞘形成包括外部因素，如在发育中发现的细胞外基质(ECM)分子 大脑。与神经元相比，少突胶质细胞的受体和信号机制知之甚少。 来规范与ECM的相互作用。我们研究的长期目标是了解在多大程度上 细胞外基质调节髓鞘形成并确定细胞外基质信号如何导致髓鞘形成的表型变化 细胞。在目前的提案中，我们将检验ECM分子层粘连蛋白增强 少突胶质细胞通过特异性跨膜受体和 信号效应器分子。我们将首先确定层粘连蛋白的少突胶质细胞受体需求 使用几种方法来单独干扰或增加少突胶质细胞中单个受体的相互作用 与神经元共同培养。层粘连蛋白需要Fyn激酶来增强少突胶质细胞的存活和 分化，但这一要求背后的分子机制尚不清楚。我们将测试 层粘连蛋白通过干扰Fyn的实验调节Fyn调控机制的假说 调控分子以及监控层粘连蛋白激活的FYN调控机制。最后， 我们将使用层粘连蛋白的模型在体内测试Fyn调节机制是否受层粘连蛋白的调节 导致CMSdysmelation的缺陷。这些研究旨在揭示脑出血的关键机制。 触发和调节少突胶质细胞存活过程的相互轴突-神经胶质信号事件， 分化和髓鞘形成。 我们希望发现刺激髓鞘形成的信号，这是一个特殊的脑细胞产生 一种被称为髓鞘的绝缘体，对神经元的生存和功能是必要的。在这样做的时候，我们可以 了解在髓鞘存在的多发性硬化症等疾病中，哪些信号缺失或被扰乱 被摧毁，并可能学习如何在阿尔茨海默氏症等神经退行性疾病中保护神经元。

Myelination is essential for brain development and function but the precise mechanisms that control the development of myelinating oligodendrocytes are not known. In demyelinating diseases such as multiple sclerosis, the loss of myelin is also thought to contribute to neurodegeneration. Myelin abnormalities of unknown origin are also found in autism, schizophrenia, and Alzheimer's disease. Candidates to regulate myelination include extrinsic factors such as extracellular matrix (ECM) molecules found in the developing brain. In contrast to neurons, little is known about the oligodendrocyte receptors and signaling mechanisms that regulate interactions with ECM. The long term goal of our research is to understand to what degree ECM regulates myelination and to determine how ECM signals lead to phenotypic changes in myelinating cells. In the current proposal we will test the hypothesis that the ECM molecule laminin enhances the survival and differentiation of oligodendrocytes by acting through specific transmembrane receptors and signaling effector molecules. We will first determine the oligodendrocyte receptor requirements for laminins using several approaches to disrupt or addback individual receptor interactions in oligodendrocytes alone or in coculture with neurons. Fyn kinase is required for laminin to enhance oligodendrocyte survival and differentiation, but the molecular mechanisms underlying this requirement are not known. We will test the hypothesis that laminins modulate Fyn regulatory mechanisms using experiments designed to disrupt Fyn regulatory molecules as well as to monitor Fyn regulatory mechansims that are activated by laminins. Finally, we will test whether Fyn regulatory mechanisms are modulated by laminins in vivo using a model for laminin deficiency that causes CMSdysmyelination. These studies are designed to uncover key mechanisms in the reciprocal axonal-glial signaling events that trigger and regulate the processes of oligodendrocyte survival, differentiation, and myelination. We hope to discover signals that stimulate myelination, a process where specialized brain cells produce an insulation, termed myelin, that is necessary for the survival and function of neurons. In doing so, we may learn which of these signals are missing or scrambled in diseases such as Multiple Sclerosis where myelin is destroyed, and, may learn how to protect neurons in neurodegenerative diseases such as Alzheimer's.