Thyroid Hormone and Neuronal Protection

甲状腺激素(TH)对正常的大脑发育是必不可少的，也可能促进恢复和 脑损伤后神经元再生。TH主要通过核受体发挥作用， 受体α(THRA)和β(THRB)。影响大脑活动的其他因素包括 甲状腺激素(T4)在5‘-脱碘酶2型作用下的代谢、活化为三碘甲状腺原氨酸(T3) (Dio2)，由5-脱碘酶3型(Dio3)失活以逆转T3(Rt3)，这发生在神经胶质细胞中 细胞，以及Mct8转运蛋白在神经元中的摄取。创伤性脑损伤与 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水平都会降低。我们已经利用脑外伤的啮齿动物模型来演示 在损伤后1小时使用T4治疗具有保护作用，减轻水肿，并促进神经元 恢复。我们已经在体外神经元损伤模型中发现了TH的类似保护作用。 缺氧。我们将研究TH对神经元损伤的保护机制以及优化 TH的保护性治疗策略，利用脑外伤的活体啮齿动物模型。我们有初步数据 确定其表达受缺氧性神经元损伤影响的基因以及 经TH治疗后正常化。我们将确定这些基因的特征，以确定受影响的特定途径 通过这样的治疗。低氧损伤增加神经元组蛋白甲基化，这种甲基化被T3降低 治疗。我们认为这是损伤后保护T3的重要机制。我们还将 识别T3刺激的激活神经再生和抗神经元凋亡的通路 缺氧性损伤。我们将利用在体脑外伤的啮齿动物模型来确定TH在保护和保护动物体内的作用 促进脑损伤后的康复，并确定脑损伤后甲状腺激素的最佳治疗方案。 我们将使用一只全球表达T3报告的小鼠来确定特定的大脑区域 损伤后T3活性降低，以及评估损伤后全身TH治疗的反应。 我们还将通过研究TH治疗脑水肿的机制来探讨TH治疗脑水肿的机制。 对水运的监管。我们将确定最佳的甲状腺激素制剂、剂量和 促进脑损伤啮齿动物模型脑功能恢复和神经再生的治疗方案。这个 对TH治疗的反应将包括通过成像对大脑损伤进行评估，具体到大脑区域 基因表达模式和行为研究。减少脑水肿和细胞死亡，并 促进神经元再生，应对脑损伤后起到有益的作用。这些研究 应为临床策略提供指导，使用TH来减少脑损伤和 促进经济复苏。 好了！

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. !