Selective modulation of thyroid hormone receptors to promote remyelination

描述（由申请人提供）：目前尚未批准用于多发性硬化（MS）的促进髓鞘再生和轴突保存的疗法。MS是一种慢性免疫介导的中枢神经系统（CNS）疾病，其特征在于脱髓鞘性白色物质病变、胶质瘢痕形成和轴突缺失。甲状腺激素（TH）在发育髓鞘形成中起着关键作用，但其在髓鞘再生中的作用尚未明确。在髓鞘形成过程中，TH通过核激素受体促进少突胶质细胞成熟和髓鞘形成。最近在啮齿动物脱髓鞘模型中的研究表明，TH具有促进髓鞘再生的能力，然而，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，我们将研究甲状腺激素受体选择性拟甲状腺激素GC-1是否可以促进脱髓鞘铜腙模型的恢复。我们还将调查是否少突胶质细胞祖细胞（OPC）在健康的成年人的大脑是敏感的外源性TH管理，一种可能导致异常OL分化的效果，或者如果他们只成为有害的事件，如脱髓鞘反应。有两种主要的TH受体（TR）。TR主要在心脏中表达，并负责TH的已知心脏效应，而TR主要在肝脏中表达，并参与脂质调节。TR <$和TR <$都在CNS中表达，并且已知在发育期间调节髓鞘形成。尽管TH在髓鞘形成中发挥重要作用的明确证据，我们还没有清楚地了解哪些TRs需要介导这些作用。我们有初步的数据表明，GC-1，TR选择性激动剂，可以诱导OPCs分化为髓鞘形成少突胶质细胞在体外。我们还发现在脱髓鞘的cuprizone模型中，在髓鞘再生过程中TR？的表达在体内增加。我们现在建议测试的假设，选择性激动的甲状腺激素受体的GC-1可以增强髓鞘再生后脱髓鞘损伤体内。在目标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。在目标2中，我们将探讨甲状腺激素及其受体调节健康成人脑和髓鞘再生状态下OPC分化的机制。我们假设，在成年CNS TR表达是OPC分化受到严格调节的一种机制，而在髓鞘再生过程中，TR作为内源性恢复过程的一部分被上调。所提出的实验的结果可以为GC-1在MS中的进一步临床转化提供强有力的临床前理论基础。

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.