Thyroid hormone signaling in hepatic fibrogenesis

纤维化是大多数慢性炎性疾病的病理特征。其定义为过量细胞外基质成分的积累。如果高度进行性，纤维化过程最终导致器官功能障碍和死亡。最终，在肝纤维化导致肝硬化，并增加发展肝癌的风险。专门针对纤维化发病机制的治疗策略非常少并且未被批准。慢性肝损伤触发细胞修复反应，当修复变得失调时发生肝纤维化。慢性肝损伤过程中纤维化和肝硬化的功能基础是非实质细胞如肝星状细胞的活化。甲状腺激素（三碘甲状腺原氨酸，T3和L-甲状腺素，T4）信号传导对组织和器官发育、生长、分化和代谢（包括脂质和胆固醇处理）至关重要。两种主要的甲状腺受体亚型，甲状腺激素受体α 1和β 1（TR α和TR β）具有组织特异性分布。初步数据显示，TR α和TR β在肝星状细胞中表达，并且用转化生长因子β（TGF-β）（一种促纤维化细胞因子）治疗导致肝星状细胞中TR α和TR β的下调。相反，用T3治疗消除了肝星状细胞的活化。我们的项目旨在评估甲状腺激素信号在肝纤维化中的作用。具体而言，我们将研究甲状腺激素是否以及如何调节细胞培养系统中的肝星状细胞反应。此外，它的目的是确定是否干扰甲状腺激素信号发生在慢性肝病患者。以下研究将涉及使用甲状腺激素受体特异性敲除小鼠，以确认甲状腺激素信号传导在肝脏疾病中的生理相关性。肝纤维化对社会的影响-成本，以及缺乏治疗肝纤维化的批准疗法，因此需要了解机制并确定新的治疗靶点。这一提议的结果可能会对调节肝纤维化的机制产生新的见解，并可能转化为新的治疗策略。

Fibrosis is a pathological feature of most chronic inflammatory diseases. It is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Ultimately, in the liver fibrosis leads to cirrhosis and increases the risk of developing liver cancer. Treatment strategies which specifically target the pathogenesis of fibrosis are very few and not approved. Chronic liver injury triggers cell repair response and liver fibrosis occurs when repair becomes deregulated. The functional basis for fibrosis and cirrhosis during chronic liver injury is activation of non-parenchymal cells, such as hepatic stellate cells. Thyroid hormone (triiodothyronine, T3 and L-thyroxine, T4) signaling is critical for tissue and organ development, growth, differentiation and metabolism (including lipid and cholesterol handling) The two major thyroid receptor isoforms, thyroid hormone receptor alpha 1 and beta 1 (TRalpha and TRbeta) have tissue-specific distribution. Preliminary data show that TRalpha and TRbeta are expressed in hepatic stellate cells, and treatment with transforming growth factor beta (TGF-beta), a profibrogenic cytokine, causes downregulation of TRalpha and TRbeta in hepatic stellate cells. Conversely, treatment with T3 abrogates the activation of hepatic stellate cells. Our project aims to evaluate the role of thyroid hormone signaling in hepatic fibrogenesis. Specifically, we will study if, and how thyroid hormones modulate hepatic stellate cell responses in cell culture systems. Further it is aim to determine if perturbations in thyroid hormone signaling occur in patients with chronic liver diseases. Following studies will involve the use of thyroid hormone receptor-specific knockout mice, to confirm the physiological relevance of thyroid hormone signaling in liver disease. Impact of liver fibrosis in society - costs, and the lack of approved therapies to treat liver fibrosis, hence the need to understand mechanisms and identify novel therapeutic targets. The results of this proposal may shed new insights into the mechanisms which regulate hepatic fibrogenesis, and may translate into new therapeutic strategies.