Galectin-3 in Liver Fibrosis

描述(申请人提供)：肝星状细胞(HSC)在肝纤维化形成过程中起关键作用。吞噬肝细胞中的凋亡体诱导HSC活化，上调前胶原α1(I)和转化生长因子-β的表达。此外，最近的研究表明，HSC具有抗原提呈细胞(APC)的功能。然而，它们在肝纤维化过程中对肝脏免疫反应的调节作用还不是很清楚。Galectin-3(Galectin-3，Galectin-3)是2-半乳糖苷结合凝集素家族中的一员，具有调节细胞吞噬功能，也是一种重要的免疫调节因子。根据我们的初步数据，Gal3是肝纤维化的重要介质，因为Gal3缺乏的HSC表现出吞噬活性降低和促纤维化活性减弱，Gal3-/-小鼠出现纤维化减轻。因此，我们的假设是Gal3通过调节HSC的吞噬和抗原递呈以及随后的免疫反应而在肝纤维化中发挥作用。为了验证这一假说，我们的具体目标是1)研究Gal3调节吞噬功能的机制，2)Gal3在肝纤维化免疫反应中的调节作用，3)Gal3在体内对肝纤维化形成和免疫调节的影响。此外，我们将在体内纤维化模型中使用Gal3抑制剂修饰的柑橘果胶(MCP)来评估其抗纤维化活性。这些研究可能导致旨在逆转或预防肝纤维化的新治疗方式的开发。

DESCRIPTION (provided by applicant): Hepatic stellate cells (HSC) play a crucial role during liver fibrogenesis. Phagocytosis of apoptotic bodies from hepatocytes induces HSC activation with upregulation of procollagen alpha 1(I) and TGF-ß expression. In addition, recent data indicate that HSC behave as antigen presenting cells (APC). However, their role in the regulation of hepatic immune responses during fibrogenesis is not well understood. Galectin-3 (Gal3), a member of 2-galactoside-binding lectin family is known to regulate cell phagocytosis and also is an important immune regulator. According to our preliminary data Gal3 is an important mediator of liver fibrosis as Gal3 deficient HSC displayed decreased phagocytic activity and diminished profibrogenic activity and Gal3-/- mice developed decreased fibrosis. Therefore, our hypothesis is that Gal3 plays a role in liver fibrosis by regulating HSC phagocytosis and antigen presentation, and the subsequent immune responses. To test this hypothesis, our specific aims are 1) to study the mechanisms by which Gal3 regulates phagocytosis, 2) the role of Gal3 in the regulation of immune responses during liver fibrosis, and 3) the in vivo effects of Gal3 on profibrogenesis and immunoregulation will be studied. In addition, we will use the Gal3 inhibitor modified citrus pectin (MCP) in the in vivo fibrosis model to assess its antifibrogenic activity. These studies may lead to the development of new therapeutic modalities aimed at reversing or preventing liver fibrosis.