FGF Receptor in Myelin Function and Disease

项目摘要 髓鞘生成是多种因素和细胞类型的复杂协调，包括少突胶质细胞 (OLS)，中枢神经系统的髓鞘细胞。成纤维细胞生长因子家族由22个成员组成 细分为7个亚科。它们作用于4个受体(R)，其中3个在OL中表达。我们的 中心模型是，成纤维细胞生长因子信号是髓鞘形成的许多方面的重要调节因素，并且 OL对FGFs的发育调节的多重反应是由于特定的 成纤维细胞生长因子/成纤维细胞生长因子受体对，每一对在谱系的每个阶段都贡献了总表型的一个子集。 这种精心策划的模式的中断会导致髓鞘病理及其伴随的神经风险。 在本项目期间，我们将更深入地研究这一fgf系统的调控机制。 髓鞘生成和脱髓鞘疾病的具体步骤。提出了三个具体目标。 在目的I中，我们研究了成纤维细胞生长因子受体信号在OL发育和髓鞘形成和维持中的作用。使用 一系列cre/lox条件性基因敲除小鼠的特异性成纤维细胞生长因子受体信号的中断，我们研究了三个 髓鞘形成的关键方面，(1)出生后的OL分化和髓鞘组装，(2)髓鞘的维持 (3)胚胎发育过程中OL祖细胞的产生。 在AIM II中，我们研究了OL系细胞中成纤维细胞生长因子/成纤维细胞生长因子受体的相互作用。使用优先激活的FGFs 特定的成纤维细胞生长因子受体和受体特异性阻断抗体，我们检验了在OL谱系期间的假设 在进展过程中，细胞被特定的FGFs差异激活，导致选择性激活特定的， 在发育过程中表达成纤维细胞生长因子受体，引起特定阶段的细胞反应。 在目标III中，我们研究了成纤维细胞生长因子受体在脱髓鞘疾病中的作用，这是建立在越来越多的共识基础上的 信号可能在脱髓鞘疾病中发挥重要作用。使用铜试剂和溶血磷脂模型 将脱/重新髓鞘作用应用于我们的Cre lox条件成纤维细胞生长因子-R突变体(Aim I)，我们检验了以下假设：成纤维细胞生长因子-1 在OL中，以细胞自主的方式发出的信号是调节的分子机制的重要组成部分 脱髓鞘的进展，以及再生髓鞘的恢复。 这个项目的长期目标是理解严格控制的 成纤维细胞生长因子受体在组织分化和髓鞘生物发生过程中的发育表达 如在髓鞘膜上的功能、维护和修复，并将这些知识应用到知情的 干预治疗多发性硬化症等脱髓鞘疾病。项目叙事 该项目的长期目标是了解 成纤维细胞生长因子在发育过程中的严格调控表达 少突胶质细胞分化为髓鞘过程中的成纤维细胞生长因子受体 生物发生，以及在髓鞘膜功能、维护和修复方面， 并将这一知识应用于知情干预治疗 多发性硬化症等脱髓鞘疾病 疾病。阐明成纤维细胞生长因子信号在这些过程中的作用 期望为知情的临床干预做出贡献，以鼓励 重新髓鞘形成和/或阻止脱髓鞘。

Project Summary Myelinogenesis is a complex orchestration of multiple factors and cell types, including Oligodendrocytes (OLs), the myelinating cells of the CNS. The Fibroblast Growth Factor (FGF) family consists of 22 members subdivided into 7 sub-families. They act on a group of 4 Receptors (Rs), 3 of which are expressed in OLs. Our central model is that FGF signaling is an important regulator of numerous aspects of myelinogenesis, and that the developmentally-regulated, multiple responses of OLs to FGFs are due to a changing repertoire of specific FGF/FGF-R pairs, each of which contributes a subset of the overall phenotype at each stage of the lineage. Interruption of this carefully orchestrated pattern leads to myelin pathology with its attendant neurological risks. In this project period, we shall delve more deeply into the mechanisms by which this FGF system regulates specific steps in myelinogenesis and demyelinating disease. Three Specific Aims are proposed. In Aim I we study FGF-R signaling in OL development and myelin formation and maintenance. Using a series of cre/lox conditional knock-out mice with disruptions in specific FGF-R signaling, we investigate three key aspects of myelinogenesis, (1) postnatal OL differentiation and myelin assembly, (2) myelin maintenance during aging, and (3) OL progenitor generation during embryonic development. In Aim II, we study FGF/FGF-R interactions in OL-lineage cells. Using FGFs that preferentially activate specific FGF-Rs and receptor-specific blocking antibodies, we test the hypothesis that during OL lineage progression, cells are differentially activated by particular FGFs, leading to selective activation of specific, developmentally expressed FGF-Rs, eliciting stage-specific cellular responses. In Aim III, we study FGF-R function in demyelinating disease, building on the growing consensus that FGF signaling may play an important role in demyelinating disease. Using the cuprizone and lysolecithin models of de/remyelination applied to our Cre lox conditional FGF-R mutants (Aim I), we test the hypothesis that FGF- signaling in OLs, in a cell autonomous manner, is an important part of the molecular mechanism regulating the progression of demyelination, and the recovery with remyelination. 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. Project Narrative The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of Fibroblast Growth Factor (FGF) receptors, both during oligodendocyte 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 and other demyelinating diseases. Clarification of the role of FGF signaling in these processes can be expected to contribute to an informed clinical intervention to encourage remyelination and/or discourage demyelination.