Extracellular matrix regulation of myelination

描述（申请人提供）：髓鞘形成对大脑发育和功能至关重要，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。在诸如多发性硬化症等脱髓鞘疾病中，髓磷脂的丧失也被认为是神经退行性变的原因之一。来源不明的髓磷脂异常也见于自闭症、精神分裂症和阿尔茨海默病。调节髓鞘形成的候选者包括外在因素，如在发育中的大脑中发现的细胞外基质（ECM）分子。与神经元相反，我们对少突胶质细胞受体和调控与ECM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。在当前的提案中，我们将验证ECM分子层粘胶蛋白通过特定的跨膜受体和信号效应分子增强少突胶质细胞的存活和分化的假设。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补充单独少突胶质细胞或与神经元共培养的个体受体相互作用。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，但这种要求的分子机制尚不清楚。我们将测试层粘连蛋白调节Fyn调节机制的假设，使用旨在破坏Fyn调节分子的实验，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发育异常的层粘连蛋白缺乏模型，在体内测试Fyn调节机制是否受层粘连蛋白调节。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轴突-胶质相互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，特殊的脑细胞产生一种被称为髓鞘的绝缘物质，这是神经元存活和功能所必需的。在这样做的过程中，我们可能会了解到在髓磷脂被破坏的多发性硬化症等疾病中，哪些信号缺失或混乱，并且可能会了解如何保护神经退行性疾病（如阿尔茨海默氏症）中的神经元。

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.