Galectin-3 in Liver Fibrosis

描述（由申请方提供）：肝星状细胞（HSC）在肝纤维化发生过程中起关键作用。吞噬来自肝细胞的凋亡小体诱导HSC活化，并上调前胶原α 1（I）和TGF-β表达。此外，最近的数据表明，HSC的行为作为抗原呈递细胞（APC）。然而，它们在纤维化过程中调节肝脏免疫反应的作用还不清楚。半乳糖凝集素3（Galectin-3，Gal 3）是2-半乳糖苷结合凝集素家族的一员，具有细胞吞噬功能，是一种重要的免疫调节因子。根据我们的初步数据，Gal 3是肝纤维化的重要介质，因为Gal 3缺陷HSC显示出降低的吞噬活性和减少的促纤维化活性，并且Gal 3-/-小鼠发展出减少的纤维化。因此，我们假设Gal 3通过调节HSC吞噬和抗原呈递以及随后的免疫应答在肝纤维化中起作用。为了验证这一假设，我们的具体目标是1）研究Gal 3调节吞噬作用的机制，2）Gal 3在肝纤维化期间调节免疫应答的作用，以及3）将研究Gal 3对促纤维化和免疫调节的体内作用。此外，我们将在体内纤维化模型中使用Gal 3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发展。

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.