Extracellular matrix regulation of myelination

髓鞘形成对大脑发育和功能至关重要，但控制髓鞘形成的精确机制并不清楚。 髓鞘形成少突胶质细胞的发育是未知的。在脱髓鞘疾病，如多发性 在硬化症中，髓磷脂的损失也被认为有助于神经变性。髓鞘异常 在自闭症、精神分裂症和阿尔茨海默氏症中也发现了不明原因。候选人监管 髓鞘形成包括外源性因素，例如在发育中的髓鞘中发现的细胞外基质（ECM）分子。 个脑袋与神经元相反，对少突胶质细胞受体和信号传导机制知之甚少 调节与ECM的相互作用。我们研究的长期目标是了解 ECM调节髓鞘形成，并确定ECM信号如何导致髓鞘形成的表型变化。 细胞在目前的建议中，我们将测试ECM分子层粘连蛋白增强细胞增殖的假设。 通过特异性跨膜受体作用， 信号效应分子。我们将首先确定层粘连蛋白对少突胶质细胞受体的需求 使用几种方法来破坏或添加单独的少突胶质细胞中的个体受体相互作用， 与神经元共培养。Fyn激酶是层粘连蛋白增强少突胶质细胞存活所必需的， 分化，但这种要求的分子机制尚不清楚。我们将测试 假设层粘连蛋白调节Fyn调节机制，使用设计破坏Fyn的实验 调节分子以及监测由层粘连蛋白激活的Fyn调节机制。最后， 我们将使用层粘连蛋白模型测试Fyn调节机制是否在体内受到层粘连蛋白的调节 导致CMS髓鞘形成障碍的缺陷。这些研究旨在揭示 触发和调节少突胶质细胞生存过程的相互轴突-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，这是一个专门的脑细胞产生 一种绝缘体，称为髓磷脂，是神经元存活和发挥功能所必需的。这样做，我们可以 了解在多发性硬化症等疾病中，这些信号中的哪些丢失或混乱， 破坏，并可能学会如何保护神经元在神经退行性疾病，如阿尔茨海默氏症。

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.