Extracellular matrix regulation of myelination

髓鞘形成的细胞外基质调节

• 批准号: 7148440
• 负责人: HOLLY A COLOGNATO
• 金额: $ 19.18万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-02 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148440
• 关键词: extracellular matrix; laminin; myelination; oligodendroglia; receptor

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.

描述（由申请人提供）：髓鞘形成对脑发育和功能至关重要，但控制髓鞘形成少突胶质细胞发育的精确机制尚不清楚。在脱髓鞘疾病如多发性硬化症中，髓鞘的丢失也被认为是导致神经变性的原因。在自闭症、精神分裂症和阿尔茨海默病中也发现了来源不明的髓鞘异常。调节髓鞘形成的候选者包括外在因子，例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，少突胶质细胞受体和调节与ECM相互作用的信号传导机制知之甚少。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信号如何导致髓鞘形成细胞的表型变化。在目前的提案中，我们将测试的假设，ECM分子层粘连蛋白通过特定的跨膜受体和信号效应分子的作用，提高少突胶质细胞的存活和分化。我们将首先确定少突胶质细胞受体的层粘连蛋白的要求，使用几种方法来破坏或addback单独的少突胶质细胞或与神经元共培养的个别受体的相互作用。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，但这种需要的分子机制尚不清楚。我们将测试的假设，层粘连蛋白调节Fyn的调节机制，使用实验设计破坏Fyn的调节分子，以及监测Fyn的调节机制，激活层粘连蛋白。最后，我们将测试是否Fyn调节机制的层粘连蛋白在体内使用层粘连蛋白缺乏症，导致中枢神经系统髓鞘形成障碍的模型调制。这些研究旨在揭示相互轴突-神经胶质信号事件的关键机制，这些事件触发和调节少突胶质细胞存活、分化和髓鞘形成的过程。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绝缘的过程，称为髓鞘，这是神经元生存和功能所必需的。通过这样做，我们可以了解这些信号中的哪些在髓鞘被破坏的多发性硬化症等疾病中丢失或混乱，并且可以了解如何在神经退行性疾病如阿尔茨海默氏症中保护神经元。