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

年龄是甲状腺功能障碍临床表现的一个重要决定因素，在老龄化人口中，甲状腺激素(TH)作用紊乱的健康后果尤其相关。解释TH作用随年龄变化的分子机制尚不完全清楚。在第一个资助期，我们研究了幼年、成年和老年雄性啮齿动物在TH过剩和缺乏的条件下，年龄对器官反应和TH信号的影响。我们发现，年龄调节甲亢和甲减的表型，如能量平衡和行为，而不影响心率和心肌肥厚。基因表达分析显示，随着年龄和T4/T3血清状态的变化，TH转运体和细胞内TH信号发生了明显的器官相关变化。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症和甲状腺功能减退症患者T4-T0血清状态随年龄变化的初步证据。在第二个资助期，我们计划1)在动物模型中完整地描述年龄对器官甲状腺状态和T4-T0血清状态的影响，2)找出观察到的器官反应年龄调节的原因，并解决没有年龄影响的原因，3)在小鼠模型中研究TH相关心脏病，以合作解决老年机体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)，以确定年龄特定的血清TH状态，并确定年轻和老年患者甲状腺功能亢进和甲减的新标记物。

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.