肥胖是心力衰竭的独立危险因素。促炎蛋白S100/Calgranulins是可靠的肥胖标志物，能否直接导致肥胖及心脏损伤尚无报道。我们前期研究发现人源化过表达S100/Calgranulins小鼠（hBAC-S100）的肥胖表型在RAGE基因敲除（KO）背景下完全消失。由此我们提出假说：S100介导的慢性炎症以RAGE受体依赖性方式促进肥胖相关心脏损伤。本项目拟采用hBAC-S100与RAGEKO小鼠建立高脂诱导的肥胖模型，从心功能、大体观察、组织病理、分子标志物表达等多个层面研究S100对心肌炎症/心肌肥厚/纤维化/糖脂代谢的影响，探讨MAPK、NF-κB、AKT、AMPK信号通路机制。结合骨髓移植及髓系炎症细胞与心肌细胞共培养，联合S100抑制药物干预，验证S100/RAGE在肥胖相关心脏损伤中的作用。项目将阐明S100介导肥胖相关心脏损伤的作用与机理，为防治肥胖相关心力衰竭提供新靶点。

Obesity itself is an independent risk factor for the development of heart failure independent of other comorbid conditions. Obesity-related cardiac injury is one of the most serious complications. Chronic inflammation mediated the pathological process of obesity-related cardiac injury. The S100/Calgranulin proteins (including S100A8, S100A9 and S100A12 ) are reliable markers of inflammation and obesity. However, the specific role of S100/calgranulins in obesity-related cardiac injury is not understood. Our previous studies had found that the transgenic “humanized” mice with transgenic expression of human S100A8, S100A9 and S100A12 (hBAC-S100) developed profound central obesity, which was almostly abolished in hBAC-S100 mice lacking receptor for advanced glycation end products(RAGE). Thus, we propose the following hypothesis: S100/Calgranulins-mediated chronic inflammation promotes obesity-related cardiac injury in a RAGE-dependent manner.We aim to investigate the effects of S100/Calgranulins on obesity-related cardiac injury induced by high fat diet (HFD) using hBAC-S100 transgenic mouse and RAGE knockout mouse models. The effects of S100/calgranulins on obesity-related cardiac injury are to be analyzed by inflammation, cardiac hypertrophy, cardiac fibrosis, glucose and lipid metabolism. We will further investigate intracellular signaling pathways including MAPK, NF-κB, AKT and AMPK. The possible mechanisms by which S100/Calgranulins affect the development of obesity-related cardiac injury are to be explored from bone marrow transplantation study and co-culture study of bone marrow-derived cells expressing S100/Calgranulins with either intact RAGE signaling or with deleted RAGE signaling and cardiac myocytes. In addition, S100/Calgranulins binding compound ABR215757 will be used to test the therapy effects on obesity-related cardiac injury in HFD-fed hBAC-S100 mice. The study will increase our knowledge of the pathogenesis of obesity-related cardiac injury and might give important new insights into the therapeutic strategy of obesity- related cardiac injury and heart failure.