Molecular mechanisms of age-dependent thyroid hormone action on target tissues

年龄依赖性甲状腺激素对靶组织作用的分子机制

• 批准号: 221205480
• 负责人: Professorin Dr. Dagmar Führer-Sakel
• 金额: --
• 依托单位: Klinik für Endokrinologie und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221205480?language=en
• 关键词: Molecular; mechanisms; age; dependent; thyroid

Age is an important determinant of the clinical presentation of thyroid dysfunction and health consequences of disturbed thyroid hormone (TH) action are particularly relevant in an aging population. The molecular mechanisms that account for age-dependent changes in TH action are not fully understood. In the first funding period we have studied age-impact on organ response and TH signaling in conditions of TH excess and deprivation in young, adult and old male rodents. We found, that age modulates phenotypes of hyper- and hypothyroidism such as energy homeostasis and behaviour, while e.g. heart rate and cardiac hypertrophy was not affected. Gene expression analysis showed distinct organ-related changes in TH transporters and intracellular TH signaling in response to age and T4/T3-serum status. In the clinical setting we have established a prospective patient cohort (TSAGE cohort) and have obtained preliminary evidence for age-dependent changes in human T4-T0 serum status in endogenous hyper- and hypothyroidism. In the second funding period we plan to 1) complete characterization of age-impact on organ thyroid status and T4-T0 serum status in our animal models, 2) identify causes for observed age-modulation of organ response and address reasons for absent age impact, 3) study TH-related heart disease in a murine model in a collaboration to address a potentially fatal complication of hyperthyroidism in an old organism and 4) continue with clinical studies (ongoing TSAGE cohort and additional recruited cohorts) to define age-specific serum TH status and to identify novel markers of hyper- and hypothyroidism in young and old patients.

年龄是甲状腺功能障碍临床表现的重要决定因素，甲状腺激素（TH）作用紊乱的健康后果在老龄化人群中尤其相关。解释TH作用中年龄依赖性变化的分子机制还不完全清楚。在第一个资助期内，我们研究了年龄对器官反应和TH信号的影响，在TH过量和剥夺的条件下，年轻，成年和老年雄性啮齿动物。我们发现，年龄调节甲状腺功能亢进和减退的表型，如能量稳态和行为，而心率和心脏肥大不受影响。基因表达分析表明，TH转运蛋白和细胞内TH信号响应年龄和T4/T3血清状态的不同器官相关的变化。在临床环境中，我们建立了一个前瞻性患者队列（TSAGE队列），并获得了内源性甲状腺功能亢进和甲状腺功能减退患者T4-T0血清状态年龄依赖性变化的初步证据。在第二个资助期内，我们计划1）在我们的动物模型中完成年龄对器官甲状腺状态和T4-T0血清状态影响的表征，2）确定观察到的器官反应年龄调节的原因，并解决年龄影响不存在的原因，3）在鼠模型中研究TH相关的心脏病，以合作解决老年生物体中甲状腺功能亢进的潜在致命并发症，以及4）继续进行临床研究（正在进行的TSAGE队列和额外招募的队列），以确定年龄特异性血清TH状态，并确定年轻和老年患者甲状腺功能亢进和减退的新标志物。