Extracellular matrix regulation of myelination

髓鞘形成的细胞外基质调节

• 批准号: 7755370
• 负责人: HOLLY A COLOGNATO
• 金额: $ 36.88万
• 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 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755370
• 关键词: Alzheimer' s Disease; Autistic Disorder; Binding Sites; Biological Models; Blocking Antibodies; Brain; Cells; Coculture Techniques; Demyelinating Diseases; Development; Disease; Dystroglycan; Engineering; Environment; Event; Extracellular Matrix; Goals; Holly; Individual; Integrins; Laminin; Laminin Receptor; Lead; Learning; Mediating; Modeling; Molecular; Monitor; Multiple Sclerosis; Mus; Mutate; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Phenotype; Phosphotransferases; Play; Process; Receptor Signaling; Regulation; Research; Research Design; Research Personnel; Role; Schizophrenia; Signal Transduction; Signaling Molecule; System; Testing; brain cell; computerized data processing; design; in vivo; myelination; programs; protein-tyrosine kinase c-src; receptor; receptor binding; research study; small hairpin RNA

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.

髓鞘形成对于大脑发育和功能至关重要，但控制髓鞘形成的精确机制 髓鞘少突胶质细胞的发育尚不清楚。在多发性脱髓鞘疾病中 硬化症、髓鞘质丧失也被认为会导致神经退行性变。髓磷脂异常 自闭症、精神分裂症和阿尔茨海默病中也发现了不明原因。监管候选人 髓鞘形成包括外在因素，例如发育中的细胞外基质（ECM）分子 脑。与神经元相反，人们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到什么程度 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。在当前的提案中，我们将测试 ECM 分子层粘连蛋白增强的假设 通过特定跨膜受体的作用来促进少突胶质细胞的存活和分化 信号传导效应分子。我们首先确定少突胶质细胞受体对层粘连蛋白的要求 使用多种方法单独破坏或添加少突胶质细胞中的个体受体相互作用，或 与神经元共培养。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，但这种要求背后的分子机制尚不清楚。我们将测试 假设层粘连蛋白通过旨在破坏 Fyn 的实验来调节 Fyn 调节机制 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来测试 Fyn 调节机制是否在体内受到层粘连蛋白的调节 导致 CMS 髓鞘发育不良的缺陷。这些研究旨在揭示关键机制 触发和调节少突胶质细胞存活过程的相互轴突-神经胶质信号传导事件， 分化和髓鞘形成。 我们希望发现刺激髓鞘形成的信号，髓鞘形成是专门的脑细胞产生的过程 一种称为髓磷脂的绝缘体，对于神经元的生存和功能是必需的。这样做时，我们可以 了解在多发性硬化症等髓鞘质缺失的疾病中，哪些信号缺失或混乱 被破坏，并且可能会学习如何保护阿尔茨海默氏症等神经退行性疾病中的神经元。

项目成果

Dystroglycan Suppresses Notch to Regulate Stem Cell Niche Structure and Function in the Developing Postnatal Subventricular Zone.

• DOI: 10.1016/j.devcel.2016.07.017
• 发表时间: 2016-09-12
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: McClenahan FK;Sharma H;Shan X;Eyermann C;Colognato H
• 通讯作者: Colognato H

Tyrosine phosphatases Shp1 and Shp2 have unique and opposing roles in oligodendrocyte development.

• DOI: 10.1111/j.1471-4159.2010.06596.x
• 发表时间: 2010-04
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Kuo E;Park DK;Tzvetanova ID;Leiton CV;Cho BS;Colognato H
• 通讯作者: Colognato H

Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation.

• DOI: 10.1002/jnr.22484
• 发表时间: 2010-11-15
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Galvin, Jason;Eyermann, Christopher;Colognato, Holly
• 通讯作者: Colognato, Holly

Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.

• DOI: 10.1523/jneurosci.0888-09.2009
• 发表时间: 2009-09-23
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Relucio J;Tzvetanova ID;Ao W;Lindquist S;Colognato H
• 通讯作者: Colognato H

Glia unglued: how signals from the extracellular matrix regulate the development of myelinating glia.

• DOI: 10.1002/dneu.20966
• 发表时间: 2011-11
• 期刊: Developmental neurobiology
• 影响因子: 3
• 作者: Colognato H;Tzvetanova ID
• 通讯作者: Tzvetanova ID