Thyroid Hormone and Neuronal Protection

甲状腺激素（TH）是大脑正常发育所必需的，也可以促进恢复， 脑损伤后的神经再生TH主要通过核受体起作用， 受体α（THRA）和β（THRB）。影响大脑中TH作用的其他因素包括 代谢，通过2型5′-脱碘酶将甲状腺素（T4）活化为三碘甲状腺原氨酸（T3） （Dio 2），通过酶5-脱碘酶3型（Dio 3）失活以逆转T3（rT 3），其发生在神经胶质细胞中。 细胞，并通过Mct 8转运蛋白在神经元中摄取。创伤性脑损伤（TBI）与 炎症、代谢改变和神经元死亡。在临床研究中，血清T4和T3水平， 以及大脑中的TH水平都降低了。我们已经利用TBI的啮齿动物模型来证明 在损伤后1小时用T4治疗是保护性的，减少水肿，并促进神经元 复苏我们已经确定了类似的保护作用TH在体外模型的神经元损伤， 缺氧我们将研究TH对神经元损伤的保护机制，并优化TH对神经元损伤的保护机制。 使用TH的保护性治疗策略，利用TBI的体内啮齿动物模型。我们有初步数据 鉴定其表达受缺氧神经元损伤影响的基因和 通过TH治疗正常化。我们将描述这些基因，以确定特定的途径影响 TH治疗。低氧损伤增加神经元中组蛋白甲基化，T3可降低组蛋白甲基化 治疗我们认为这是T3在损伤后保护的重要机制。我们还将 鉴定T3刺激的激活神经再生和抗凋亡的途径， 缺氧损伤我们将利用TBI的体内啮齿动物模型来确定TH在保护和治疗TBI中的作用。 促进脑损伤后的恢复，并确定TBI后最佳的甲状腺激素治疗。 我们将使用具有T3报告基因的全局表达的小鼠来确定特定的脑区域， 损伤后减少的T3作用，以及评估损伤后对全身性TH治疗的反应。 我们还将通过研究TH治疗减轻脑水肿的机制， 水路运输的监管。我们将确定最佳的甲状腺激素制剂，剂量和 在啮齿动物TBI模型中，治疗方案促进脑恢复和神经再生。的 对TH治疗的反应将包括通过成像、脑区域特异性 基因表达模式和行为研究。TH减少脑水肿和细胞死亡，以及 促进神经元再生，应该在脑损伤后提供有益的效果。这些研究 应该为临床策略提供指导，以使用TH来减少脑损伤的影响， 促进复苏。 !

Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation of thyroxine (T4) to triiodothyronine (T3) by the enzyme 5′-deiodinase Type 2 (Dio2), inactivation by the enzyme 5-deiodinase Type 3 (Dio3) to reverse T3 (rT3), which occurs in glial cells, and uptake by the Mct8 transporter in neurons. Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and neuronal death. In clinical studies, serum levels of T4 and T3, as well as TH levels in the brain, are reduced. We have utilized rodent models of TBI to demonstrate that treatment with T4, 1 hour after injury, is protective, reduces edema, and promotes neuronal recovery. We have identified similar protective effects of TH in an in vitro model of neuronal injury from hypoxia. We will study both the mechanism of TH protection from neuronal injury as well as optimize protective treatment strategies with TH, utilizing in vivo rodent models of TBI. We have preliminary data identifying genes whose expression is impacted by hypoxic neuronal injury and those that are normalized by TH treatment. We will characterize these genes to identify specific pathways influenced by TH treatment. Hypoxic injury increases histone methylation in neurons and this is reduced by T3 treatment. We believe that this is an important mechanism for T3 protection after injury. We will also identify T3-stimulated pathways that activate neural regeneration and anti-apoptosis in neurons after hypoxic injury. We will utilize in vivo rodent models of TBI to identify the actions of TH in protection and promotion of recovery after brain injury and determine the optimal thyroid hormone treatment after TBI. We will use a mouse with global expression of a T3-reporter to determine specific brain regions with reduced T3 action after injury, as well as assess the response to systemic TH treatment after injury. We will also investigate the mechanism of TH treatment reduction in brain edema by studying the regulation of water transport. We will determine the optimal thyroid hormone preparation, dose and treatment schedule to promote brain recovery and neural regeneration in rodent models of TBI. The response to TH therapy will include assessment of the brain lesion by imaging, brain region-specific patterns of gene expression and behavioral studies. TH reduction in brain edema and cell death, and promotion of neuronal regeneration, should provide a beneficial effect after brain injury. These studies should provide guidance for clinical strategies to use TH to reduce the impact of brain injury and promote recovery. !