BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle

项目摘要 糖尿病的发生和发展涉及氧化应激和炎症， 会导致包括心肌和骨骼肌在内的多个器官的紊乱。然而，它 目前尚不清楚炎症引起的细胞死亡，即所谓的上睑下垂是否发生在 糖尿病患者的心肌和骨骼肌。我们的初步数据显示，糖尿病小鼠有 单核细胞、促炎性Toll样受体4、NLRP3炎症体、 激活caspase-1并增加心脏和骨骼中的促炎细胞因子 肌肉。重组骨形成蛋白-7(BMP-7)治疗减少 高血糖、炎症以及改善心脏和肌肉功能。基于这些 初步数据，我们假设BMP-7增加了抗炎的M2巨噬细胞 减少下垂，从而改善糖尿病患者的心脏和骨骼肌功能。我们 建议通过以下目标来检验这一假设。 1：糖尿病通过增加炎症导致心脏和骨骼肌功能障碍 细胞因子、NLRP3炎性小体激活和caspase 1调节下垂。 2：BMP-7治疗使单核细胞分化为抗炎的M2巨噬细胞 导致改善下垂和不良的心肌和骨骼肌重塑 糖尿病小鼠。 3：BMP-7慢性治疗通过抑制血管紧张素转换酶抑制减少糖尿病并发症 翻译型兔糖尿病模型中的炎症途径和下垂。 拟议的研究将在类型1和类型2的成熟模型中进行 糖尿病。我们期望阐明上睑下垂在引起心脏和骨骼的关键作用。 肌肉功能障碍和骨形态发生蛋白-7治疗在糖尿病中的有益作用。这些研究已经 对糖尿病患者重症护理的承诺，因为BMP-7已被临床批准用于 欧洲骨质疏松症患者的治疗。

Project Summary The development and progression of diabetes involves oxidative stress and inflammation that leads to disorders in multiple organs including the cardiac and skeletal muscle. However, it remains unknown whether inflammation induced cell death, known as pyroptosis occurs in cardiac and skeletal muscle of diabetics. Our preliminary data shows that diabetic mice have enhanced infiltration of monocytes, pro-inflammatory toll-like receptor 4, NLRP3 inflammasome, activated caspase-1 and increased pro-inflammatory cytokines in the heart as well as skeletal muscle. Treatment with the recombinant bone morphogenic protein-7 (BMP-7) decreased hyperglycemia, inflammation and improved cardiac and muscle function. Based on these preliminary data, we hypothesize that BMP-7 increases anti-inflammatory M2 macrophages decreases pyroptosis, thereby improving cardiac and skeletal muscle function in diabetes. We propose to test this hypothesis through the following aims. 1: Diabetes causes cardiac and skeletal muscle dysfunction through increase of inflammatory cytokines, activation of NLRP3 inflammasome and caspase 1 regulated pyroptosis. 2: Treatment with BMP-7 differentiates monocytes into anti-inflammatory M2 macrophages resulting in amelioration of pyroptosis and adverse cardiac and skeletal muscle remodeling in diabetic mice. 3: Chronic treatment with BMP-7 ameliorates diabetic complications through suppression of inflammatory pathways and pyroptosis in a translational rabbit model of diabetes. The proposed studies will be carried out in the well-established models of Type 1 and Type 2 diabetes. We expect to elucidate the critical role of pyroptosis in causing cardiac and skeletal muscle dysfunction and the beneficial role of BMP-7 therapy in diabetes. These studies have the promise for critical care of diabetic patients, because BMP-7 is clinically approved for the treatment of osteoporosis patients in Europe.