Caveolin-1/lGF-IR Interactions in Oligodendrocytes

描述(申请人提供)：多发性硬化症(MS)的特征是 通过中枢神经系统内斑块状的脱髓鞘。再髓鞘形成是 通常是不完全的，OLG未能重新髓鞘形成至少是部分原因 由于OLG程序性细胞死亡(PCD)。Caveolin-1可能对OLG进行调制 功能和生存。小窝蛋白-1构成小窝的结构主干 囊泡，在信号转导、胆固醇运输、 细胞周期调控和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)的小窝蛋白-1调节(通常 抑制)信号转导。CSD与信号的保守区结合 分子，如酪氨酸受体的小窝蛋白结合域(CBD) 激活剂。我们之前已经证明了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，这 与其他人的研究结果一致，即小窝蛋白-1的表达 依赖于差异的。小窝蛋白-1‘S在黄斑变性中的表达及作用尚未见报道 已经研究过了。胰岛素样生长因子-I在OLG中的重要作用 发展，促进OLGs的髓鞘形成和再髓鞘形成，保护OLGs PCD，并防止脱髓鞘，但潜在的分子机制 人们对此了解甚少。我们提供了小窝蛋白-1结合的初步证据 IGF-I受体(IGF-IR)含有一个可能的CBD，是酪氨酸。 IGF-IR激活后的磷酸化。我们有四个具体目标：1)分析 胰岛素样生长因子-IR信号和小窝蛋白-1-胰岛素样生长因子-IR在OLG中的相互作用 小窝蛋白-1表达及小窝蛋白1酪氨酸磷酸化对血管内皮生长因子表达的影响 IGF-IR介导的信号、增殖、分化和易感性 PCD，3)表征小窝蛋白-1-IGF-IR在OLG中的相互作用，检查对 IGFIR介导的信号、增殖、分化和PCD，以及4) 研究小窝蛋白-1-IGF-IR相互作用在活体OLG中的后果。在… 通过这些研究的结束，我们将更好地了解小窝蛋白-1‘对S的调节作用 OLGs中的IGF-IR信号和IGF-IR介导的增殖、分化和 OLG的神经保护作用。了解IGF-IR和IGF-IR之间的相互作用 Caveolin-1及其对OLG表型的控制将为深入了解 OLG髓鞘形成的分子基础，有望指导新的治疗方法 女士。

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.