Fibroblast Growth Factor Receptors in Myelin Function

描述(申请人提供)：成纤维细胞生长因子受体(R)R1、R2和R3是少突胶质细胞(OL)分化的重要调节因子。此外，R2被定位于髓鞘膜，在那里它可能在髓鞘-轴突信号转导中发挥作用。在OL分化过程中，R1、R3和R2的表达受到仔细的调控。我们假设，观察到的OL对成纤维细胞生长因子的多重反应是由于涉及R1、R2和R3的多受体现象，每一种受体在谱系的每个阶段都贡献了整个表型的一个子集。在AIM I中，我们将研究R2在我们利用CRE/IOX技术建立的R2缺失小鼠模型中的作用，在该模型中，R2的表达在髓鞘细胞中被特异性地删除。我们认为，通过R2的成纤维细胞生长因子信号在调节OL的终末分化和髓鞘的生物发生、维持和功能中发挥作用，包括轴突信号。初步数据表明，这些小鼠在OL分化和髓鞘-轴突相互作用方面有显著变化。在AIM II中，我们研究了在OL发育过程中调节的成纤维细胞生长因子受体表达的功能意义，应用了新的工具，包括激活特定的成纤维细胞生长因子受体，从R3和R2缺乏的小鼠培养的成骨细胞，以及SH2图谱来识别特定的成纤维细胞生长因子受体激活的可能的下游靶点。在AIM III中，我们注意到体内OL的发育是由多种细胞类型产生的多种因素的平衡协调。我们建议研究成纤维细胞生长因子在体内的作用，通过其所有受体协同作用的信号，通过低刺激或高刺激成纤维细胞生长因子受体。在这些研究的背景下，我们建议在R2和R3缺失的小鼠中引入局灶性脱髓鞘，以研究这些受体在重新髓鞘形成和修复中的作用。该项目的长期目标是了解在OL分化导致髓鞘生物发生以及髓鞘膜功能、维持和修复过程中严格受控的成纤维细胞生长因子受体表达的功能意义，并将这一知识应用于多发性硬化症等脱髓鞘疾病的知情干预治疗。

DESCRIPTION (provided by applicant): Fibroblast Growth Factor (FGF) Receptors (R) R1, R2 and R3 are important regulators of oligodendrocytes (OL) differentiation. Further, R2 is targeted into the myelin membrane, where it may play a role in myelin-axon signaling. The expression of R1, R3 and R2 is carefully regulated during OL differentiation. We hypothesize that the observed multiple responses of OLs to FGF are due to multi-receptor phenomena involving R1, R2 and R3, each of which contributes a subset of the overall phenotype at each stage of the lineage. In AIM I we will examine the role of R2 in an R2-null mouse model we have developed using cre/Iox technology, in which R2 expression is deleted specifically in myelinating cells. We propose that FGF signaling via R2 plays a role in both the regulation of OL terminal differentiation and myelin biogenesis, maintenance and function, including axoglial signaling. Preliminary data indicate that these mice have significant alterations in OL differentiation and myelin-axon interactions. In AIM II we investigate the functional significance of regulated FGF Receptor expression during OL development, applying new tools including FGFs that activate specific FGF receptors, OL cultured from R3- and R2-deficient mice, and SH2 profiling to identify likely down-stream targets of specific FGF receptor activation. In AIM III we note that OL development in vivo is a balanced orchestration of multiple factors produced by multiple cell types. We propose to study the role of FGF in vivo in the context of signaling through all its receptors acting in concert, by either hypostimulating or hyperstimulating the FGF receptors. Against the background of these studies, we then propose to introduce focal demyelination in R2- and R3- null mice in order to study the role of these receptors in remyelination and repair. The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of FGF receptors both during OL differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as Multiple Sclerosis.