FGF Receptor in Myelin Function and Disease

描述（由申请人提供）：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个受体（Rs），其中3个在ol中表达。我们的中心模型是FGF信号是髓鞘形成的许多方面的重要调节因子，并且发育调节的OLs对FGF的多重反应是由于特定FGF/FGF- r对的变化，每个FGF/FGF- r对在谱系的每个阶段贡献了整体表型的一个子集。这种精心安排的模式中断会导致髓磷脂病理及其伴随的神经系统风险。在本项目期间，我们将更深入地研究FGF系统调控髓鞘形成和脱髓鞘疾病具体步骤的机制。提出了三个具体目标。在Aim I中，我们研究了FGF-R信号在OL发育和髓磷脂形成和维持中的作用。我们使用一系列cre/lox条件敲除小鼠，并破坏特定的FGF-R信号，研究髓鞘形成的三个关键方面，(1)出生后的OL分化和髓磷脂组装，(2)衰老过程中的髓磷脂维持，以及(3)胚胎发育过程中的OL祖细胞生成。在Aim II中，我们研究了ol谱系细胞中FGF/FGF- r的相互作用。利用优先激活特定FGF-Rs和受体特异性阻断抗体的FGFs，我们验证了在OL谱系进展过程中，细胞被特定FGFs差异激活的假设，导致特异性的、发育中表达的FGF-Rs选择性激活，引发特定阶段的细胞反应。在Aim III中，我们研究了FGF- r在脱髓鞘疾病中的功能，基于FGF信号可能在脱髓鞘疾病中发挥重要作用的共识。我们将铜酮和溶索磷脂模型应用于我们的Cre - lox条件FGF- r突变体（Aim I），验证了OLs中FGF-信号以细胞自主的方式是调节脱髓鞘进展和髓鞘再生的分子机制的重要组成部分。该项目的长期目标是了解严格控制FGF受体的发育表达在OL分化导致髓鞘生物发生以及髓鞘膜功能，维持和修复中的功能意义，并将这些知识应用于治疗脱髓鞘疾病（如多发性硬化症）的知情干预。该项目的长期目标是了解严格控制成纤维细胞生长因子（FGF）受体发育表达的功能意义，无论是在导致髓鞘生物生成的少突胶质细胞分化过程中，还是在髓鞘膜功能、维持和修复过程中。并将这些知识应用到脱髓鞘疾病的知情干预治疗中，如多发性硬化症和其他脱髓鞘疾病。澄清FGF信号在这些过程中的作用，有望有助于知情的临床干预，以促进髓鞘再生和/或阻止脱髓鞘。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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 oligodendrocyte 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.