Thyroid hormone signaling in hepatic fibrogenesis

肝纤维化中的甲状腺激素信号传导

• 批准号: 276096991
• 负责人: Dr. Paul Manka
• 金额: --
• 依托单位: Liver Regeneration and Repair Research Group
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/276096991?language=en
• 关键词: Thyroid; hormone; signaling; hepatic; fibrogenesis

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.

纤维化是大多数慢性炎症性疾病的病理特征。它的定义是过量的细胞外基质成分的积累。如果进展很快，纤维化过程最终会导致器官功能障碍和死亡。最终，肝纤维化会导致肝硬变，增加患肝癌的风险。专门针对纤维化发病机制的治疗策略很少，也没有得到批准。慢性肝损伤触发细胞修复反应，当修复变得不受控制时，就会发生肝纤维化。慢性肝损伤时肝纤维化和肝硬变的功能基础是非实质细胞的激活，如肝星状细胞。甲状腺激素(三碘甲腺原氨酸，T3和L-甲状腺素，T4)信号对组织和器官的发育、生长、分化和代谢(包括脂质和胆固醇的处理)至关重要。甲状腺激素受体的两个主要亚型，甲状腺激素受体α1和β1(TRa和Trbeta)具有组织特异性分布。初步研究表明，肝星状细胞表达TRα和TRβ，转化生长因子β是一种促纤维化细胞因子，经治疗后，肝星状细胞中TRα和TRβ的表达下调。相反，用T3治疗可以取消肝星状细胞的激活。我们的项目旨在评估甲状腺激素信号在肝纤维化形成中的作用。具体地说，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，其目的是确定慢性肝病患者是否存在甲状腺激素信号的扰动。接下来的研究将涉及使用甲状腺激素受体特异性基因敲除小鼠，以确认甲状腺激素信号在肝脏疾病中的生理相关性。肝纤维化对社会的影响--成本，以及缺乏已批准的治疗肝纤维化的疗法，因此需要了解机制并确定新的治疗靶点。这一建议的结果可能为调节肝纤维化形成的机制提供新的见解，并可能转化为新的治疗策略。