人CCR2新的高亲和力配体PSMP的表达，及其在肝病非可控炎症恶性转化中作用和机制的研究

The framework of the human genome map has been completed 10 years. Still a lot of functions of new human gene encoding protein need to be explored. Chemokines and their receptors have become the frontiers of basic medicine, translational medicine, as well as innovative drug discovery. Against this background, we carried out original research to identify potential new chemokines from protein-coding genes in the human genome. Five new potential chemokines have received by screening. One of them is PSMP, which is a secreted protein by prostate cancer cell line PC3. PSMP is able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B expressing THP-1 cells and its functional receptor is identified as CCR2B. PSMP has a very high level of expression in cirrhosis and adjacent non-tumor and distant metastasis of liver cancer. Nonresolving inflammation plays an important role in the pathological process of liver cirrhosis and cancer. The role of CCR2 ligands in inflammation and malignant transformation has also been widespread concern. On this basis, this project will clarify functions and mechanisms of PSMP in malignant transformation of nonresolving inflammatory liver disease at the molecular level, cellular level, the overall level of animal and clinical level, and discover new drug targets, which is expected to have important theoretical significance and application value.

人类基因组框架图已完成10年，仍有大量的人类基因编码蛋白功能有待我们发掘。趋化因子及其受体已经成为生物基础医学、转化医学研究以及创新药物发现的前沿领域。基于这一背景，我们原创地开展了从人类基因组编码基因中发现潜在的新趋化因子，经筛选获得5个新的人潜在趋化因子，PSMP是其中之一，是一种可被前列腺癌细胞系PC3分泌的蛋白。PSMP对外周血单核细胞、淋巴细胞、THP-1细胞具有趋化作用，我们实验证实PSMP是一个可通过CCR2发挥其趋化功能的新趋化细胞因子。PSMP在肝硬化、肝癌旁、肝远端转移癌中有非常高水平的表达。非可控性炎症在肝硬化、肝癌发生发展的病理过程中发挥着重要作用，CCR2及配体在炎症恶性转化中的作用也受到了广泛关注。在此基础上，本课题申请将在分子水平、细胞水平、动物整体和临床水平阐明PSMP在肝病非可控炎症恶性转化中作用和机制，发现新的药物作用靶点，具有重要的理论意义和应用价值。

人类基因组框架图已完成10余年，仍有大量的人类基因编码蛋白功能有待发掘。趋化因子及其受体已成为生物基础医学、转化医学研究以及创新药物发现的前沿领域。基于这一背景，我们原创地开展了从人类基因组编码基因中发现潜在的新趋化因子，经筛选获得5个新的人潜在趋化因子，PSMP是其中之一，可被前列腺癌细胞系PC3分泌。PSMP对外周血单核细胞、淋巴细胞、THP-1细胞具有趋化作用，我们实验证实PSMP是一个可通过CCR2发挥其趋化功能的新趋化细胞因子。进一步研究发现PSMP在多诱因肝硬化、肝癌旁、肝远端转移癌中有非常高水平的表达。我们构建了PSMP敲除小鼠。通过体内外功能和机制研究揭示PSMP在CCl4和BDL诱导的肝纤维化发生发展的病理过程中发挥着重要作用，其作用是CCR2依赖的。另一方面，我们原创构建的PSMP单克隆抗体能够预防和治疗性抑制肝纤维化发生发展。本课题首次揭示PSMP是肝纤维化防治新靶点，PSMP单克隆抗体是一潜在创新药物，具有重要的理论意义和广阔的应用前景。