糖尿病心肌病是糖尿病的常见并发症之一，流行病学研究发现70％的糖尿病患者死于此并发症。P53活化造成的心肌细胞凋亡和老化，是诱导糖尿病心肌病的前导因素。此外前期工作发现糖尿病后期FGF21表达迅速降低，可能与糖尿病心肌病的发生发展相关。但是糖尿病状态下FGF21与P53关系以及FGF21在保护糖尿病心肌病的作用仍不明确。进一步机制研究发现FGF21对心，肝，肾P53活性具有负调控作用，同时证实肝脏和肾脏中存在FGF21与P53的复合物。另外FGF21可激活去乙酰化酶SIRT1也能间接抑制P53的活性。据此我们提出科学假设：在心脏中FGF21能通过直接结合或通过激活去乙酰化酶途径负调控P53活性从而预防1型糖尿病心肌病。我们将引入多种转基因小鼠并配合体外研究解析FGF21和P53的关系以及FGF21对糖尿病心肌病的保护效应

Diabetic cardiomyopathy (DCM) is the main complications in type 1 diabetic patients.P53 induced cardiac apoptosis and senescence are considered as the previous pathological features of type 1 DCM. Our preliminary studies demonstrated that at the late-stage of diabetes, the cardiac fibroblast growth factor (FGF)-21 mRNA expression significantly decreased, which may enhance the development of DCM. More importantly，its relationship of FGF21 with P53 in protecting the mechanism of DCM is still not clear. Additionally, we found that FGF21 negtively regulats P53 acitivity in the heart,liver and kidney. An complex of FGF21 with P53 was further detected in the liver and kidney. Moreover, P53 activity was appreciated to be indirectly influenced by deacetylation enzyme SIRT1. Therefore, we forward a new hypothesis that FGF21 negtively regulates cardiac P53 activity either by formation of complex with P53 or by activation of deacetylation enzyme SIRT1. In this project a few of gene knock-out mice will be applied, in combination of in vitro studies, to verify the relationship of FGF21 with P53 and the protection by FGF21 from type 1 DCM.