骨髓干细胞分泌因子KIAA1199对骨和脂肪分化以及代谢的调控

人类各种器官组织间的相互作用和调节是重要的科学问题。骨和骨髓干细胞，作为近年确认的内分泌组织，如何通过其分泌因子调控其他组织和全身代谢还所知甚少。我们在前期研究中鉴定到骨和骨髓干细胞的一个新型分泌因子KIAA1199（也称CEMIP），发现它在干细胞的成骨分化和成脂分化中呈现不同的表达分泌变化，但该因子如何调控干细胞的不同的谱系分化，以及它会如何利用分化调控组织功能和全身代谢尚不清楚。本项目拟以骨髓干细胞不同谱系分化模型为基础，着重研究KIAA1199对成骨和成脂分化的调节，并进一步在自己构建的基因敲除小鼠上，分析该因子对骨骼、脂肪和其他重要器官的功能和基因调控，并特别检测在高脂诱导的肥胖和糖尿状态下KIAA1199 对糖脂代谢，胰岛素抵抗的调控。阐述KIAA1199调控干细胞分化的分子机理，并为KIAA1199靶向抑制剂或抗体在肥胖及糖尿病的治疗作用提供理理论和实践基础。

The complex interactions and crosstalk between different tissues and organs require further exploration. In particular, bone and bone marrow, increasingly appreciated as endocrine organs, regulate other tissues and systemic metabolism through poorly understood cell secreted factors. We recently identified KIAA1199 (also named as Cell Migration Inducing Hyaluronidase 1, CEMIP) as a novel bone and bone marrow stem cell secreted factor. Notably, it exhibits different expression patterns during osteogenic differentiation and adipogenic differentiation in human stromal stem cells. Yet how KIAA1199 may regulate stem cell lineage designation, plus its role during bone and fat formation and systemic metabolism remains to be established. We aim to take advantage of a powerful well-established human bone marrow stromal stem cell (hBMSC) differentiation model to further understand the role of KIAA1199 in osteogenesis and adipogenesis. Use of proprietary gene knockout mice, will allow analysis of the metabolic regulation of CEMIP in bone, fat and other tissues. Moreover, we will also test the regulation of glucose and lipid metabolism, and insulin resistance by KIAA1199 in high-fat-diet induced obesity models. This project will advance our knowledge of molecular mechanisms, determining how KIAA1199 modulates key signaling pathways governing hBMSC differentiation; exploring the potential therapeutic effects of KIAA1199 targeted inhibitors or antibodies in obesity and metabolic diseases.