Extracellular matrix regulation of myelination

描述(申请人提供)：髓鞘形成是大脑发育和功能所必需的，但控制髓鞘形成的少突胶质细胞发育的确切机制尚不清楚。在多发性硬化症等脱髓鞘疾病中，髓鞘的丢失也被认为是导致神经退化的原因之一。原因不明的髓鞘异常也可见于自闭症、精神分裂症和阿尔茨海默病。调节髓鞘形成的候选因素包括外部因素，如在发育中的大脑中发现的细胞外基质(ECM)分子。与神经元相比，少突胶质细胞受体和调节与细胞外基质相互作用的信号机制知之甚少。我们研究的长期目标是了解ECM在多大程度上调节髓鞘形成，并确定ECM信号如何导致髓鞘细胞的表型变化。在目前的方案中，我们将检验这一假设，即ECM分子层粘连蛋白通过特定的跨膜受体和信号效应分子发挥作用，从而增强少突胶质细胞的存活和分化。我们将首先使用几种方法来确定少突胶质细胞对层粘连蛋白的受体需求，这些方法单独或与神经元共同培养时中断或增加单个受体的相互作用。Fyn激酶是层粘连蛋白增强少突胶质细胞存活和分化所必需的，但这一要求背后的分子机制尚不清楚。我们将通过实验验证层粘连蛋白调节FYN调节机制的假设，该实验旨在破坏FYN调节分子以及监测由层粘连蛋白激活的FYN调节机制。最后，我们将使用导致中枢神经系统髓鞘功能障碍的层粘连蛋白缺乏的模型，在体内测试Fyn调节机制是否受层粘连蛋白的调节。这些研究旨在揭示触发和调节少突胶质细胞存活、分化和髓鞘形成过程的相互轴突-神经胶质信号事件的关键机制。我们希望发现刺激髓鞘形成的信号，在这个过程中，专门的脑细胞产生一种被称为髓鞘的绝缘物质，这是神经元生存和功能所必需的。通过这样做，我们可能会了解到在多发性硬化症等髓鞘被破坏的疾病中，哪些信号缺失或被扰乱，并可能了解如何在阿尔茨海默氏症等神经退行性疾病中保护神经元。

DESCRIPTION (provided by applicant): 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 mechanisms 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 CNS dysmyelination. 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.