Selective modulation of thyroid hormone receptors to promote remyelination

选择性调节甲状腺激素受体以促进髓鞘再生

基本信息

批准号：
8554391
负责人：
PETER A CALABRESI
金额：
$ 19.54万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554391
关键词：
Acute Adult Adverse effects Agonist Animal Model Axon Binding Biological Preservation Body Weight decreased Brain Cardiac Cell Differentiation process Central Nervous System Diseases Cerebellar cortex structure Cerebral cortex Cholesterol Chronic Cicatrix Clinical Clinical Trials Corpus Callosum Cuprizone Data Demyelinations Development Disease Electron Microscopy Event GC 1 compound Goals Gray unit of radiation dose Heart Hippocampus (Brain)Human Immune Immune System Diseases In Vitro Kinetics Lead Lesion Lipids Liver Measurement Mediating Modeling Multiple Sclerosis Mus Muscle Weakness Myelin Myelin Sheath Neuraxis Neurologic Nuclear Hormone Receptors Numbness Oligodendroglia PDGFRB gene Pathway interactions Pharmaceutical Preparations Phase Physiologic pulse Play Process Protein Isoforms Protocols documentation Recovery Regulation Reporting Research Project Grants Research Proposals Rodent Model Role Spinal cord damage Stem cells Symptoms Tachyphylaxis Testing Therapeutic Intervention Thyroid Hormone Receptor Thyroid Hormones Tissues Translations Up-Regulation Visual Western Blotting brain cell chronic demyelination design disability feeding hormone therapy in vivo myelination oligodendrocyte lineage overexpression pre-clinical public health relevance receptor receptor expression remyelination repaired research study treatment duration white matter young adult

项目摘要

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.

描述（由适用提供）：目前尚无对多发性硬化症（MS）的批准疗法，可促进延期性和轴突保存。 MS是一种慢性免疫介导的中枢神经系统（CNS）的疾病，其特征是白质病变，神经胶质疤痕形成和轴突丧失。甲状腺激素（THS）在发育髓鞘中起着至关重要的作用，但是尚未明确定义它们在透明度中的作用。在发育性髓鞘中，通过核马酮受体来促进少突胶质细胞的成熟和髓鞘形成。在啮齿动物脱髓鞘模型中的最新研究表明，THS具有促进再生性的能力，但是对TH受体的非特异性刺激也会产生明显的不明显的副作用。在该研究项目中，我们将调查甲状腺马酮受体是否有选择性的甲状腺甲状腺素GC-1可以促进脱髓鞘模型中的恢复。我们还将调查健康成人大脑中的少突胶质细胞祖细胞（OPC）是否对外源性TH敏感，这种作用可能导致异常分化，或者仅在损伤事件（例如脱髓鞘）后才变成反应性。有两个主要受体（TR）。 TR主要在心脏中表达，并负责THS的已知心脏作用，而TR主要在肝脏中表达，并参与脂质调节。 TRO和Trâ均在中枢神经系统中表达，并在发育过程中调节髓鞘形成。尽管明确证明TH在髓鞘中起着重要作用，但我们尚未清楚地了解哪些TR需要哪些TR来调节这些效果。我们有初步数据表明，GC-1是一种选择性激动剂，可以在体外诱导OPC分化为髓磷脂形成少突胶质细胞。我们还发现，在脱髓鞘模型中，Tr tr tr tr tr s表达会增加体内的体内。现在，我们建议检验以下假设：ta肌酮受体的选择性激动剂在体内脱髓鞘损伤后可以增强透明度。在AIM 1中，我们将研究GC-1在急性和慢性脱髓鞘场景中增强再生的潜力。在AIM 2中，我们将探讨甲状腺骑术及其受体在健康的成年大脑和透明状态下调节OPC分化的机制。我们假设在成年中枢神经系统中，TR表达是一种机制，通过该机制受到严格调节的一种机制，而在Remerelination期间，TR tr被上调为内源性恢复过程的一部分。提出的实验的结果可以为MS中GC-1的进一步临床翻译提供强大的临床前原理。