The nonthyroidal illness syndrome

描述（由申请人提供）：非甲状腺疾病综合征（NTIS），也称为病态正常甲状腺综合征，是与任何急性或慢性疾病相关的血清甲状腺激素（T3）浓度低的状态，无下丘脑-垂体-甲状腺轴的内在疾病。NTIS的严重程度与疾病的严重程度直接相关，多项研究表明，NTIS的严重程度是死亡率的独立和强有力的预测因素。这些研究的长期目标是了解NTIS的潜在机制，并解决是否应该进行治疗，如果是这样，应该采取什么治疗方法。第一个具体目标将使用细胞培养和体内小鼠模型来解决甲状腺素转化为T3的降低的机制，这是NTIS的特征。已知1型碘甲状腺原氨酸脱碘酶（D1）的活性和表达会因疾病而降低。这种效应至少部分是由于甲状腺激素受体诱导D1基因Dio 1转录的能力缺陷。将研究缺陷D1表达、低血清T3和甲状腺激素受体辅激活因子功能之间的关系。具体目标2将使用两种体内NTIS小鼠模型（内毒素给药和脓毒症）来测试特定治疗（甲状腺激素受体辅激活剂的强制表达）是否可以改善NTIS并降低死亡率。具体目标3将评价NTIS中甲状腺激素受体辅激活因子功能受损的基础。待探索的细胞因子或疾病相关的潜在机制包括诱导与辅激活因子竞争的辅抑制因子、辅激活因子向其他基因的再分布、辅激活因子向细胞其他区域的再分布以及辅激活因子的翻译后修饰异常。非甲状腺疾病综合征（NTIS）的严重程度与疾病的严重程度直接相关，多项研究表明，NTIS的严重程度是死亡率的独立和强有力的预测因素。这些研究将探讨NTIS的治疗是否能改善严重医学疾病的康复。

DESCRIPTION (provided by applicant): The nonthyroidal illness syndrome (NTIS), also called the sick euthyroid syndrome, is the state of a low serum thyroid hormone (T3) concentration associated with any acute or chronic illness, without intrinsic disease of the hypothalamic-pituitary-thyroid axis. The severity of the NTIS correlates directly with the severity of illness, and multiple studies show that the severity of the NTIS is an independent and powerful predictor of mortality. The long term objectives of these studies are to understand the mechanisms underlying the NTIS and to address whether it should ever be treated, and if so, what the treatment should be. The first Specific Aim will use cell culture and in vivo mouse models to address the mechanisms underlying the decreased conversion of thyroxine to T3 that characterizes the NTIS. The activity and expression of type 1 iodothyronine deiodinase (D1) are known to be decreased by illness. This effect is due at least in part to a defective ability of thyroid hormone receptors to induce transcription of the D1 gene, Dio1. The relationship between defective D1 expression, the low serum T3, and thyroid hormone receptor coactivator function will be investigated. Specific Aim 2 will use two in vivo mouse models of NTIS, endotoxin administration and sepsis, to test whether a specific therapy (forced expression of a thyroid hormone receptor coactivator) can ameliorate the NTIS and decrease mortality rate. Specific Aim 3 will evaluate the basis for impaired thyroid hormone receptor coactivator function in the NTIS. Cytokine or illness-associated potential mechanisms to be explored include induction of corepressors that compete with the coactivators, redistribution of coactivators to other genes, redistribution of coactivators to other regions of the cell, and abnormalities in post-translational modifications of coactivators. The severity of the nonthyroidal illness syndrome (NTIS) correlates directly with the severity of illness, and multiple studies show that the severity of the NTIS is an independent and powerful predictor of mortality. These studies will address whether treatment of the NTIS improves recovery from serious medical illnesses.