The Role of Neurotrophins in Oligodendrocyte Function

 描述(申请人提供)：在多发性硬化症(MS)中，少突胶质细胞(一种在轴突周围产生绝缘髓鞘的细胞)功能障碍并死亡，导致脱髓鞘。许多组织正在寻找能够逆转这种破坏的分子。在我们之前的资助期间完成的研究表明，BDNF是一种分子，可以促进从一种类型的脱髓鞘中恢复，这种脱髓鞘的试剂是铜试剂[1，2]。此外，BDNF定位于病变部位的细胞。为了研究我们如何增强这些细胞来源的BDNF的合成和释放，并潜在地促进病变的恢复，在我们最近的研究中，我们检查了一些与病变部位相关的递质系统的影响。特别是，我们的实验表明，代谢性谷氨酸受体(MGluRs)在脱髓鞘条件下发挥保护作用[3]。这一观察结果与其他研究其他退化情况的人一致[4，5]。此外，这些mGluR在包括多发性硬化症在内的许多脑部疾病中表达上调，这表明它们的重要性可能在损伤条件下被强调[6-9]。在我们的研究中，我们报告了BDNF在代谢激动剂acpd治疗后被释放，并引起髓鞘蛋白的增加。ACPD通过与病变部位的星形胶质细胞(AST)上的mGluR相互作用来做到这一点[3]。新的结果进一步表明，BDNF和MBP的升高是外周和脑内注射I组mGluR激动剂相关的Acpd，CHPG的结果。此外，最近的数据表明，外周注射CHPG可以改善EAE的临床症状，这是MS的第二个脱髓鞘模型。这些新数据提出了一种令人兴奋的可能性，即mGluR激动剂可以通过AST来源的BDNF的中介逆转脱髓鞘缺陷。这些激动剂可以外周应用来诱导这种逆转。我们提出的工作就是为了测试这种可能性。首先，由于Acpd的作用相对一般，我们将继续确定注射后最能引起BDNF和髓鞘特征增加的特定受体。其次，我们将确定CHPG在促进少突胶质细胞成熟的脱髓鞘损伤部位的细胞作用。第三，我们将确定CHPG在阻止与免疫反应和脱髓鞘表型相关的EAE模型进展方面的作用。

 DESCRIPTION (provided by applicant): In Multiple Sclerosis (MS) the oligodendrocyte (a cell that produces an insulating myelin sheath around axons) becomes dysfunctional and dies, resulting in demyelination. Many groups are searching for molecules that can reverse this destruction. Studies completed during the tenure of our previous grant revealed that BDNF is one molecule that enhanced recovery from one type of demyelination that is elicited by the agent, cuprizone [1, 2]. Moreover, BDNF was found localized to cells in the lesion site. To examine how we might enhance BDNF synthesis and release from these cellular sources and potentially enhance recovery from a lesion, in our recent studies we examined effects of a number of transmitter systems affiliated with the lesion site. In particular, our experiments revealed that metabotropic glutamate receptors (mGluRs) play protective roles under demyelination conditions [3]. This observation is consistent with those of others looking at other degenerative conditions [4,5]. Moreover, these mGluRs are upregulated in a number of brain diseases, including MS, suggesting that their importance may be accentuated under conditions of injury [6-9]. In our studies we report that BDNF is released after treatment with a metabotropic agonist, ACPD, and elicits increases in myelin proteins. ACPD does so by interacting with mGluRs on astrocytes (ASTs) in the lesion site [3]. New results suggest further that BDNF and MBP elevations result from peripheral, as well as brain injections of the Group I mGluR agonist relative of ACPD, CHPG. In addition, recent data suggest that peripheral injections of CHPG ameliorate clinical signs of EAE, a second demyelinating model of MS. These new data raise the exciting possibility that mGluR agonists can reverse demyelinating deficits through the mediation of AST-derived BDNF. The agonists can be applied peripherally to elicit this reversal. Our proposed work is designed to test this possibility. First, since ACPD can be relatively general in its actions, we will continue to identify the specific receptors that best elicit increases in BDNF and myelin traits upon injection. Second, we will identify the cellular roles of CHPG in the demyelination lesion site that promote oligodendrocyte maturation. Third we will identify roles of CHPG that prevent progression of the EAE model that is affiliated with an immune response as well as a demyelinating phenotype.