FGF Receptor in Myelin Function and Disease

描述(申请人提供)：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)，即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，分为7个亚家族。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子，而成纤维细胞生长因子受发育调节的多种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-R对的变化所致，每一对都在谱系的每个阶段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。在这个项目期间，我们将更深入地研究成纤维细胞生长因子系统调节髓鞘形成和脱髓鞘疾病的具体步骤的机制。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。我们利用一系列特定的成纤维细胞生长因子受体信号中断的cre/lox条件性基因敲除小鼠，研究了髓鞘发生的三个关键方面，(1)出生后的OL分化和髓鞘组装，(2)衰老过程中的髓鞘维持，以及(3)胚胎发育期间的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。使用优先激活特定的成纤维细胞生长因子受体和受体特异性阻断抗体的成纤维细胞生长因子，我们检验了这一假设，即在OL谱系发展过程中，细胞被特定的成纤维细胞生长因子差异激活，导致特定的、发育中表达的成纤维细胞生长因子受体的选择性激活，引发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，建立在越来越多的共识基础上，即成纤维细胞生长因子信号可能在脱髓鞘疾病中发挥重要作用。使用我们的Cre lox条件性成纤维细胞生长因子-R突变体(Aim I)的铜酮和溶血磷脂脱髓鞘模型，我们验证了假设，即成纤维细胞生长因子信号以细胞自主的方式在成骨细胞中是调节脱髓鞘进展和再生髓鞘恢复的分子机制的重要组成部分。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。公共卫生相关性本项目的长期目标是了解成纤维细胞生长因子受体在导致髓鞘生物生成的少突胶质细胞分化过程中以及在髓鞘膜功能、维护和修复过程中的功能意义，并将这一知识应用于对多发性硬化症和其他脱髓鞘疾病等脱髓鞘疾病的知情干预治疗。阐明成纤维细胞生长因子信号在这些过程中的作用有望有助于进行知情的临床干预，以鼓励重新髓鞘形成和/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.