FGF Receptor in Myelin Function and Disease

FGF 受体在髓磷脂功能和疾病中的作用

• 批准号: 7911968
• 负责人: RASHMI BANSAL
• 金额: $ 6.28万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911968
• 关键词: Aging; Blocking Antibodies; Cells; Clinical; Complex; Consensus; Cuprizone; Defect; Demyelinating Diseases; Demyelinations; Development; Disease; Elderly; Embryo; Embryonic Development; FGF2 gene; Family; Family member; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Generations; Goals; Growth Factor Receptors; Interruption; Intervention; Knockout Mice; Knowledge; Lysophosphatidylcholines; Maintenance; Membrane; Modeling; Molecular; Multiple Sclerosis; Myelin; Neuroepithelial Cells; Neurologic; Oligodendroglia; Pathology; Pattern; Phenotype; Play; Process; Prosencephalon; Recovery; Regulation; Risk; Role; Series; Signal Transduction; Staging; System; Testing; cell type; human FGF3 protein; in vivo; member; mutant; myelin biogenesis; oligodendrocyte lineage; postnatal; preference; progenitor; public health relevance; receptor; repaired; response

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.

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（OL），CNS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，再分为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。我们的中心模型是FGF信号传导是髓鞘形成的许多方面的重要调节剂，并且OL对FGF的发育调节的多重响应是由于特定FGF/FGF-R对的变化库，其中每一个在谱系的每个阶段贡献整体表型的子集。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。在这个项目期间，我们将更深入地研究FGF系统调节髓鞘形成和脱髓鞘疾病中特定步骤的机制。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，在特定的FGF-R信号转导中断，我们研究了髓鞘形成的三个关键方面，（1）出生后OL分化和髓鞘组装，（2）老化过程中髓鞘的维持，和（3）胚胎发育过程中OL祖细胞的产生。在目的II中，我们研究了OL系细胞中FGF/FGF-R的相互作用。使用优先激活特定FGF-R和受体特异性阻断抗体的FGF，我们检验了以下假设：在OL谱系进展期间，细胞被特定FGF差异激活，导致特异性发育表达的FGF-R的选择性激活，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上，即FGF信号传导可能在脱髓鞘疾病中起重要作用。使用应用于我们的Cre lox条件性FGF-R突变体（Aim I）的脱髓鞘/再髓鞘化的铜腙和溶血素模型，我们测试了以下假设：OL中的FGF信号传导以细胞自主方式是调节脱髓鞘化进展和再髓鞘化恢复的分子机制的重要部分。该项目的长期目标是了解在导致髓鞘生物发生的OL分化期间以及在髓鞘膜功能、维护和修复中FGF受体的严格控制的发育表达的功能意义，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成纤维细胞生长因子（FGF）受体的严格控制的发育表达的功能意义，包括在导致髓鞘生物发生的少突胶质细胞分化期间，以及在髓鞘膜功能、维护和修复中，并将该知识应用于脱髓鞘疾病如多发性硬化症和其它脱髓鞘疾病的治疗中的知情干预。FGF信号在这些过程中的作用的澄清，可以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。