Caveolin-1/lGF-IR Interactions in Oligodendrocytes

少突胶质细胞中的 Caveolin-1/lGF-IR 相互作用

• 批准号: 6701805
• 负责人: DANIEL D MIKOL
• 金额: $ 17.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701805
• 关键词: apoptosis; biological signal transduction; caveolins; cell differentiation; cell proliferation; gene expression; genetic susceptibility; genetically modified animals; growth factor receptors; histogenesis; insulinlike growth factor; laboratory mouse; myelination; nerve /myelin protein; neuroprotectants; oligodendroglia; phosphorylation; protein protein interaction; protein structure function; receptor binding; tissue /cell culture; transfection; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is characterized by patchy demyelination within the central nervous system. Remyelination is often incomplete, and the failure of OLGs to remyelinate is at least in part due to OLG programmed cell death (PCD). Caveolin-1 is likely to modulate OLG function and survival. Caveolin-1 forms the structural backbone of caveolae vesicles and has diverse effects on signal transduction, cholesterol transport, cell cycle control, and PCD. By binding to signaling proteins via a region termed the caveolinscaffolding domain (CSD), caveolin-1 regulates (generally inhibits) signal transduction. The CSD binds to conserved regions of signaling molecules, such as the caveolin-binding domain (CBD) of receptor tyrosine kinases. We have previously shown that caveolin-1 expression by Schwann cells increases during development and decreases following nerve transection, which is consistent with findings by others that caveolin-1 expression is differentiation-dependent. Caveolin-1's expression and function in OLGs has not been studied. Insulinlike growth factor I (IGF-I) plays a vital role in OLG development, enhancing myelination and remyelination by OLGs, protecting OLGs from PCD, and preventing demyelination, but the underlying molecular mechanisms are poorly understood. We provide preliminary evidence that caveolin-1 binds to the IGF-I receptor (IGF-IR), contains a putative CBD, and is tyrosine phosphorylated following IGF-IR activation. We have 4 Specific Aims: 1) Analyze IGF-IR signaling and caveolin-1-IGF-IR interactions in OLGs, 2) investigate the effects of caveolin-1 expression and caveolin-1 tyrosine phosphorylation on IGF-IR-mediated signaling, proliferation, differentiation, and susceptibility to PCD, 3) characterize caveolin-1-IGF-IR interactions in OLGs, examining effects on IGFIRmediated signaling, proliferation, differentiation and PCD, and 4) investigate the consequences of caveolin-1-IGF-IR interactions in OLGs in vivo. At the end of these studies, we will better understand caveolin-1's regulation of IGF-IR signaling in OLGs and IGF-IR mediated proliferation, differentiation and neuroprotection of OLGs. Understanding the interplay between the IGF-IR and caveolin-1 and their control of OLG phenotype will provide insight into the molecular basis of myelination by OLGs and, hopefully, guide new treatments for MS.

描述（由申请人提供）：多发性硬化症（MS）的特征是 中枢神经系统内的斑片状脱髓鞘再髓鞘化是 通常是不完全的，OLG的髓鞘再生失败至少部分是因为 程序性细胞死亡（PCD）。Caveolin-1可能调节OLG 功能和生存。小窝蛋白-1形成小窝的结构骨架 囊泡，并对信号转导，胆固醇转运， 细胞周期控制和PCD。通过一个区域与信号蛋白结合 被称为小窝蛋白支架结构域（CSD），小窝蛋白-1调节（通常 抑制）信号转导。CSD与信号传导的保守区域结合， 分子，如受体酪氨酸的小窝蛋白结合结构域（CBD） 激酶。我们先前已经证明雪旺细胞表达小窝蛋白-1， 在发育过程中增加，在神经切断后减少， 与其他人的发现一致，即小窝蛋白-1表达是 依赖于分化。Caveolin-1在OLG中的表达和功能尚不清楚， 本文研究了胰岛素样生长因子I（IGF-I）在OLG中起重要作用 通过OLG促进髓鞘形成和髓鞘再生，保护OLG 防止脱髓鞘，但潜在的分子机制 我们对此知之甚少。我们提供的初步证据表明，小窝蛋白-1结合， IGF-I受体（IGF-IR），含有推定的CBD，并且是酪氨酸 在IGF-IR活化后磷酸化。我们有四个具体目标：1）分析 OLG中IGF-IR信号传导和小窝蛋白-1-IGF-IR相互作用，2）研究OLG中IGF-IR信号传导和小窝蛋白-1-IGF-IR相互作用。 小窝蛋白-1表达和小窝蛋白-1酪氨酸磷酸化对 IGF-IR介导的信号传导、增殖、分化和对 PCD，3）表征OLG中小窝蛋白-1-IGF-IR相互作用，检查对 IGFIR介导的信号传导、增殖、分化和PCD，以及4） 研究小窝蛋白-1-IGF-IR相互作用在体内OLG中的后果。在 这些研究的结束，我们将更好地了解小窝蛋白-1的调控， OLG中的IGF-IR信号传导和IGF-IR介导的增殖、分化和细胞增殖。 OLG的神经保护了解IGF-IR和 小窝蛋白-1和它们对OLG表型的控制将提供对 OLG髓鞘形成的分子基础，并有望指导新的治疗方法， 女士