Thyroid Hormone and Neuronal Protection

甲状腺激素和神经元保护

• 批准号: 9888202
• 负责人: GREGORY A BRENT
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888202
• 关键词: Adult; Aftercare; Apoptosis; Area; Brain; Brain Edema; Brain Injuries; Brain imaging; Brain region; Cell Culture Techniques; Cell Death; Cell Line; Clinical; Clinical Research; DNA Methylation; DNA Methylation Regulation; Data; Development; Differentiation and Growth; Dose; Edema; Enzymes; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Grant; Growth; High Prevalence; Hour; Hypoxia; Image; In Vitro; Inflammation; Injury; Iodide Peroxidase; Lead; Lesion; Mediating; Metabolic; Metabolism; Modeling; Modification; Morbidity - disease rate; Mus; Natural regeneration; Nerve Regeneration; Neuroglia; Neuronal Differentiation; Neuronal Hypoxia; Neuronal Injury; Neurons; Nuclear Receptors; Pathogenesis; Pathway interactions; Population; Preparation; Recovery; Regimen; Regulation; Reporter; Rodent; Rodent Model; Sampling; Screening procedure; Serum; Study of serum; TBI treatment; Therapeutic; Thyroid Hormones; Thyroid hormone receptor alpha; Thyroxine; Traumatic Brain Injury; Treatment Protocols; Triiodothyronine; Veterans; Water; behavioral study; brain cell; epigenetic regulation; histone methylation; histone modification; hormone therapy; in vitro Model; in vivo; mortality; nerve injury; nerve stem cell; neuron loss; protective effect; relating to nervous system; response; response to injury; tissue injury; treatment strategy; uptake

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. !

甲状腺骑马（Th）对于正常的大脑发育至关重要，也可能促进康复和 脑损伤后神经元再生。这主要通过核接收器起作用 受体α（THRA）和β（THRB）。影响大脑行动的其他因素包括 代谢，甲状腺素（T4）通过酶5'-二碘酶2型的三碘甲醇（T3）的激活（T3） （dio2），酶5-二二二氨二酶3（dio3）灭活至反向T3（RT3），该酶发生在胶质中 细胞，以及MCT8转运蛋白在神经元中的摄取。创伤性脑损伤（TBI）与 在临床研究中，血清T4和T3水平， 以及大脑中的TH水平降低。我们已经利用TBI的啮齿动物模型来证明 受伤后1小时的T4治疗受到保护，减少水肿并促进神经元 恢复。我们已经确定了TH在从 缺氧。我们将研究保护免受神经元损伤的保护机制，并优化 使用TBI的体内啮齿动物模型，使用TH的保护性处理策略。我们有初步数据 识别其表达受到低氧神经损伤影响的基因 通过TH治疗归一化。我们将表征这些基因以识别受影响的特定途径 通过治疗。低氧损伤增加了神经元中的组蛋白甲基化，这被T3降低了 治疗。我们认为，这是受伤后T3保护的重要机制。我们也会 确定激活神经元再生和抗凋亡神经元后神经元的途径 低氧损伤。我们将利用TBI的体内啮齿动物模型来确定TH在保护和 促进脑损伤后恢复，并确定TBI后最佳的甲状腺马酮治疗。 我们将使用带有T3 reporter全局表达的鼠标来确定特定的大脑区域 受伤后T3作用降低，并评估受伤后对系统治疗的反应。 我们还将通过研究 调节水运输。我们将确定最佳的甲状腺激素制剂，剂量和 在TBI啮齿动物模型中促进脑恢复和中性再生的治疗时间表。这 对TH疗法的反应将包括通过成像，大脑特异性对脑病变的评估 基因表达和行为研究的模式。脑水肿和细胞死亡的减少，以及 神经元再生的促进应在脑损伤后产生有益的作用。这些研究 应该为临床策略提供指导，以减少脑损伤的影响和 促进康复。 呢