Receptor-mediated effects on oligodendrocyte phenotype and disease

受体介导对少突胶质细胞表型和疾病的影响。 本研究的目的是确定影响少突胶质细胞发育和分化的erbB家族和肿瘤坏死因子家族受体之间的相互作用。肿瘤坏死因子家族成员被认为与多发性硬化症(MS)的OL死亡有关，我们假设它们的活性影响OL细胞上Erb B受体成员的功能。我们将使用各种方法来确定这些受体家族配对关系的生化基础，以及它们如何在体外和体内引导由erbB配体驱动的成熟。在努力的过程中，我们希望确定与OL前体细胞有丝分裂生长最相关的信号通路，以及那些导致OL细胞成熟的信号通路。将尝试将OL的分化与细胞周期蛋白依赖性激酶抑制物的积聚联系起来。大分子治疗在体内修饰肿瘤坏死因子活性的努力 单枪匹马是不成功的。我们开发了一类新的二级结构外环肽和半胱氨酸结的模拟物，可能会以一种有利于MS治疗的方式限制肿瘤坏死因子受体信号，特别是如果与erbB生长因子受体激活结合在一起的话。这种由肿瘤坏死因子受体结构设计的新的二级结构外环物和胱氨酸结形式将在体内用于改变实验性变态反应性脑脊髓炎(Eae)中免疫驱动的少突胶质细胞死亡。 模特。在这些研究过程中，与罗斯塔米博士、愉悦博士和陈博士的广泛合作将是重要的。这些研究解决的基本原则可能与多发性硬化症的治疗相关。

Receptor-mediated effects on oligodendrocyte phenotype and disease. The objectives of this ongoing continuation are to define the paired interactions of the erbB family and TNF family of receptors that influence the development and differentiation of oligodendrocytes (OL). TNF family members are thought relevant to OL death in multiple sclerosis (MS), and we hypothesize that their activity influences the function of erbB receptor members on OL cells. We will use a variety of approaches to determine the biochemical basis of the paired relationship of these receptor families and how they guide maturation driven by erbB ligands in vitro and in vivo. In the course of the efforts we hope to identify signaling pathways that are most relevant to mitotic growth of OL precursors and those that lead to maturation to functional OL cells. Attempts will be made to correlate differentiation of OL with cyclin dependent kinase inhibitor accumulation. Efforts to modify TNF activity in vivo by macromolecular therapy alone have been unsuccessful. We have developed a novel class of secondary structure exocyclic peptides and cystine knot mimetics that may limit TNF receptor signaling in a way beneficial to MS therapy, especially if coupled to erbB growth factor receptor activation. This new class of secondary structural exocyclics and cystine knot forms designed from the TNF receptor structure will be used in vivo in attempts to modify the immunologically driven oligodendrocyte death seen in the experimental allergic encephalomyelitis (EAE) model. Extensive collaborations with Dr. Rostami, Dr. Pleasure, and Dr. Chen will be important during the course of these studies. Basic principles resolved by these studies may have relevance to multiple sclerosis therapy.