Selective modulation of thyroid hormone receptors to promote remyelination

描述（由申请人提供）：目前还没有批准的治疗多发性硬化症（MS）的促进髓鞘再生和轴突保存的疗法。多发性硬化症是一种慢性免疫介导的中枢神经系统疾病，以脱髓鞘白质病变、胶质瘢痕形成和轴突丧失为特征。甲状腺激素（THs）在发育髓鞘形成中起关键作用，但其在髓鞘再生中的作用尚未明确定义。在发育性髓鞘形成过程中，THs通过核激素受体促进少突胶质细胞成熟和髓鞘形成。最近对啮齿动物脱髓鞘模型的研究表明，TH具有促进脱髓鞘再生的能力，但对TH受体的非特异性刺激也会产生显著的不良副作用。在本研究项目中，我们将研究一种甲状腺激素受体选择性拟甲状腺激素GC-1是否能促进铜酮脱髓鞘模型的恢复。我们还将研究健康成人大脑中的少突胶质祖细胞（OPCs）是否对外源性TH给药敏感，这种影响可能导致异常的OL分化，或者它们是否仅在损伤事件（如脱髓鞘）后才变得反应性。有两种主要的TH受体（TRs）。TR主要在心脏中表达，并负责已知的th对心脏的影响，而TR¿主要在肝脏中表达，并参与脂质调节。TR¿和TR¿都在中枢神经系统中表达，已知在发育过程中调节髓鞘形成。尽管有明确的证据表明TH在髓鞘形成中起重要作用，但我们还不清楚哪些tr需要介导这些作用。我们有初步的数据显示GC-1，一种TR -选择性激动剂，可以在体外诱导OPCs向髓鞘形成的少突胶质细胞分化。我们还发现，在铜盐脱髓鞘模型中，TR¿在体内的表达在脱髓鞘过程中增加。我们现在提出验证GC-1对甲状腺激素受体的选择性激动作用可以在体内促进脱髓鞘损伤后的再脱髓鞘形成的假设。在目的1中，我们将研究GC-1在急性和慢性脱髓鞘情况下增强髓鞘再生的潜力。在目的2中，我们将探讨甲状腺激素及其受体在健康成人大脑和髓鞘再生状态下调节OPC分化的机制。我们假设，在成人中枢神经系统中，TR表达是OPC分化受到严格调控的一种机制，而在髓鞘再生过程中，TR表达作为内源性恢复过程的一部分被上调。本实验结果为GC-1在MS中的进一步临床转化提供了强有力的临床前理论依据。

DESCRIPTION (provided by applicant): There are currently no approved therapies for Multiple Sclerosis (MS) that promote remyelination and axon preservation. MS is a chronic immune-mediated disease of the central nervous system (CNS) characterized by demyelinating white matter lesions, glial scar formation and axonal loss. Thyroid hormones (THs) play a critical role in developmental myelination, however their role in remyelination has not yet been clearly defined. During developmental myelination THs act through nuclear hormone receptors to promote oligodendrocyte maturation and myelination. Recent studies in rodent models of demyelination suggest that THs have the capacity to promote remyelination, however non-specific stimulation of TH receptors can also produce significant undesirable side-effects. In this research project, we will investigate if a thyroid hormone receptor ¿ selective thyromimetic, GC-1, can promote recovery in the cuprizone model of demyelination. We will also investigate whether oligodendrocyte progenitor cells (OPCs) in the healthy adult brain are sensitive to exogenous TH administration, an effect that could lead to aberrant OL differentiation, or if they only become reactive following injurious events, such as demyelination. There are two major TH receptors (TRs). TR is predominantly expressed in the heart and is responsible for the known cardiac effects of THs, whereas TR¿ is predominantly expressed in the liver and is involved in lipid regulation. Both TR¿ and TR¿ are expressed in the CNS and are known to modulate myelination during development. Despite unequivocal evidence of the important role played by TH in myelination, we do not yet clearly understand which TRs are required to mediate these effects. We have preliminary data showing that GC-1, a TR¿ selective agonist, can induce differentiation of OPCs into myelin forming oligodendrocytes in vitro. We also find that TR¿ expression increases in vivo during remyelination in the cuprizone model of demyelination. We now propose to test the hypothesis that selective agonism of the ¿ thyroid hormone receptor by GC-1 can enhance remyelination following a demyelinating insult in vivo. In aim 1 we will investigate the potential for GC-1 to enhance remyelination in both acute and chronic demyelination scenarios. In aim 2 we will explore the mechanisms by which thyroid hormones and their receptors regulate OPC differentiation in both the healthy adult brain and in the remyelinating state. We hypothesize that in the adult CNS TR expression is one mechanism by which OPC differentiation is tightly regulated, whereas during remyelination TR¿ is up-regulated as part of the endogenous recovery process. The results of the proposed experiments could provide strong preclinical rationale for the further clinical translation of GC-1 in MS.