The nonthyroidal illness syndrome

非甲状腺疾病综合征

• 批准号: 8090377
• 负责人: RONALD Jay KOENIG
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090377
• 关键词: Accounting; Acetylation; Acute; Address; Adenoviruses; Animals; Cell Culture Techniques; Cells; Chronic Disease; Defect; Development; Endotoxins; Enzymes; Euthyroid Sick Syndromes; Gene Deletion; Genes; Genetic Transcription; Hepatocyte; Human; Hypothalamic Diseases; Iodothyronine Deiodinase; Knockout Mice; Ligands; Ligation; Lipopolysaccharides; Medical; Methylation; Modeling; Mus; Operative Surgical Procedures; Outcome; Phosphorylation; Post-Translational Protein Processing; Puncture procedure; Recovery; Role; Sepsis; Serum; Severities; Severity of illness; Syndrome; Testing; Thyroid Hormone Receptor; Thyroxine; Triiodothyronine; Triiodothyronine Receptors; base; cytokine; improved; in vivo; iodothyronine deiodinase type I; mortality; mouse model; nuclear receptor coactivator 1; pituitary thyroid axis; prevent; promoter; response

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.

描述（由申请人提供）：非甲状腺疾病综合征（NTIS），也称为病态的甲状腺综合征，是低血清甲状腺激素（T3）浓度低的状态，与任何急性或慢性疾病相关，而没有固有性疾病的甲状腺甲状腺 - 甲状腺 - 甲状腺 - 甲状腺 - 甲状腺 - 甲状腺轴。 NTI的严重程度与疾病的严重程度直接相关，多项研究表明，NTI的严重程度是死亡率的独立和强大的预测指标。这些研究的长期目标是了解NTI的基础机制并解决是否应该得到治疗，如果是这样，则应是什么治疗方法。第一个特定的目的将使用细胞培养和体内小鼠模型来解决甲状腺素向T3降低的机制，该机制表征了NTI的特征。已知1型碘甲氧氨酸脱碘酶（D1）的活性和表达被疾病降低。这种作用至少部分是由于甲状腺激素受体诱导D1基因DiO1转录的能力。 D1表达缺陷，低血清T3和甲状腺激素受体共激活因子功能之间的关系将进行研究。具体目标2将使用两种NTI的体内小鼠模型，内毒素给药和败血症，以测试特定的治疗（甲状腺激素受体共激活剂）是否可以改善NTI并降低死亡率。具体目标3将评估NTI中甲状腺激素受体共激活剂功能受损的基础。要探索的细胞因子或与疾病相关的潜在机制包括诱导与共激活剂竞争的核压剂，共激活因子重新分布到其他基因，将共激活因子重新分布到其他区域的其他区域，以及在共同激活器后转移剂中进行异常。非甲状腺疾病综合征（NTI）的严重程度与疾病的严重程度直接相关，多项研究表明，NTI的严重程度是死亡率的独立而有力的预测指标。这些研究将解决NTI的治疗是否可以改善严重的医学疾病的康复。