FGF Receptor in Myelin Function and Disease

项目摘要 髓鞘形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形成细胞。成纤维细胞生长因子（FGF）家族由22个成员组成 分为7个亚家族。它们作用于一组4种受体（Rs），其中3种在OL中表达。我们 中心模型是FGF信号传导是髓鞘形成的许多方面的重要调节剂， 发育调节的OL对FGF的多种反应是由于特定的 FGF/FGF-R对，其中每一个在谱系的每个阶段贡献总体表型的子集。 这种精心策划的模式的中断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保证基金制度的监管机制， 髓鞘形成和脱髓鞘疾病的特定步骤。提出了三个具体目标。 在目的I中，我们研究了OL发育和髓鞘形成和维持中的FGF-R信号传导。使用 一系列cre/lox条件性基因敲除小鼠的特异性FGF-R信号转导被破坏，我们研究了三种 髓鞘形成的关键方面，（1）出生后OL分化和髓鞘组装，（2）髓鞘维持 在老化过程中，和（3）在胚胎发育过程中的OL祖代。 在目的II中，我们研究了OL系细胞中FGF/FGF-R的相互作用。使用优先激活 特异性FGF-Rs和受体特异性阻断抗体，我们检验了在OL谱系中 进展时，细胞被特定的FGF差异性激活，导致特异性， 发育表达的FGF-R，引发阶段特异性细胞应答。 在目的III中，我们研究了FGF-R在脱髓鞘疾病中的功能，建立在越来越多的共识，即FGF 信号传导可能在脱髓鞘疾病中起重要作用。使用铜腙和溶血素模型， 脱髓鞘/再髓鞘应用于我们的Cre lox条件性FGF-R突变体（目的I），我们测试了FGF-1在脱髓鞘/再髓鞘中的作用的假设。 在OLs中，以细胞自主方式的信号传导是调节细胞凋亡的分子机制的重要组成部分。 脱髓鞘的进展和髓鞘再生的恢复。 本项目的长期目标是了解严格控制的功能意义 在OL分化过程中FGF受体的发育表达导致髓鞘生物发生，以及 如髓磷脂膜功能，维护和修复，并将这些知识应用于一个知情的 干预治疗脱髓鞘疾病，如多发性硬化症。项目叙述 本项目的长期目标是了解 严格控制成纤维细胞生长因子的发育表达 (FGF)受体，在寡树突细胞分化过程中导致髓鞘 生物发生，以及髓鞘膜功能，维护和修复， 并将这一知识应用于治疗 脱髓鞘疾病如多发性硬化和其它脱髓鞘疾病 疾病阐明FGF信号传导在这些过程中的作用， 预期有助于知情的临床干预，以鼓励 髓鞘再生和/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.