The Role of Neurotrophins in Oligodendrocyte Function

描述(申请人提供)：在体内和培养中影响少突胶质细胞(OLG)谱系细胞存活和发育的各种生长因子可能会影响白质疾病中少突胶质细胞(OLG)退化或重新髓鞘形成的程度(Gao，Gillig等人)。2000年；Mason，Suzuki等人。2001年；阿姆斯特朗，勒等人。2002年；Murtie，周等人。2005)。我们的结果表明，这些分子之一是脑源性神经营养因子(BDNF)。我们实验室在上一次资助期间的工作表明，BDNF通过TrkB的调节影响培养中OLG亚群的增殖和分化。此外，BDNF+/-小鼠表现出MBP+髓磷脂分布和在胼胝体中发育的NG2+前体细胞减少。初步研究表明，它们也表现出钝性的NG2增加和MBP降低，作为对铜酮诱导的脱髓鞘损伤的反应。基于这些结果，我们假设在脱髓鞘损伤后，BDNF通过TrkB的介导，直接增加OLG前体细胞的增殖和OLG分化，影响OLG的再髓鞘形成。特别是，我们建议1)使用BDNF+/-小鼠来研究BDNF在铜带损伤模型中增加OLG祖细胞数量和OLG谱系细胞分化方面的作用，2)通过评估外源性BDNF对铜带损伤后OLG再生和受损的影响来研究BDNF的治疗潜力，3)验证BDNF促进增殖和分化，但不影响生存的假设，并且OLG谱系细胞上的TrkB介导BDNF的作用。公共卫生相关性：在脱髓鞘疾病中，有少突胶质细胞的丢失，少突胶质细胞为神经元提供绝缘鞘。这一应用的研究旨在评估生长因子BDNF在脱髓鞘损伤期间和之后促进少突胶质细胞系细胞的发育、存活和功能方面的作用。这项工作可能导致BDNF作为一种治疗剂的发展，并为遗传学家鉴定潜在的候选基因，以测试这些毁灭性疾病的易感基因。

DESCRIPTION (provided by applicant): A variety of growth factors that impact survival and development of oligodendrocyte (OLG) lineage cells in vivo and in culture may affect the extent of degeneration or remyelination of oligodendrocytes (OLGs) in white matter disease (Gao, Gillig et al. 2000; Mason, Suzuki et al. 2001; Armstrong, Le et al. 2002; Murtie, Zhou et al. 2005). Our results suggest that one of these molecules is brain derived neurotrophic factor (BDNF). Work in our lab during the previous funding period indicates that BDNF, through the mediation of TrkB, influences proliferation and differentiation of OLG subpopulations in culture. In addition, BDNF +/- mice exhibit decreases in MBP+ myelin profiles and NG2+ progenitors that develop in the corpus callosum. Preliminary studies suggest that they also exhibit blunted increases in NG2 and reduced MBP in response to a cuprizone-elicited demyelinating lesion. Based on these results, we hypothesize that following a demyelinating lesion, BDNF, through the mediation of trkB, directly increases OLG progenitor proliferation and OLG differentiation, impacting OLG remyelination. In particular, we propose to 1) use BDNF +/- mice to examine the role of BDNF in increasing numbers of OLG progenitors and differentiation of OLG lineage cells in the cuprizone injury model, 2) investigate the therapeutic potential of BDNF by evaluating effects of exogenous BDNF on regenerating and damaged OLGs following a cuprizone lesion, 3) test the hypothesis that BDNF acts to enhance proliferation and differentiation, but not to influence survival, and that TrkB on OLG lineage cells mediates BDNF action. PUBLIC HEALTH RELEVANCE: In demyelinating diseases there is a loss of oligodendrocytes, cells that provide insulating sheaths to neurons. Studies of this application are designed to evaluate roles of the growth factor BDNF in promoting development, survival and function of oligodendrocyte lineage cells during and after a demyelinating lesion. This work may lead to the development of BDNF as a therapeutic agent and to the identification of potential candidate genes for geneticists to test as susceptibility loci for these devastating diseases.