HIF-1/P53表达水平转换介导增生性瘢痕自噬和自噬性死亡的机制研究

前期研究发现：在增生性瘢痕演变过程中存在中、重度缺血动态缺氧，同时伴随自噬、自噬性死亡发生，以及HIF-1/p53表达水平的转变和beclin-1的相应变化。自噬是细胞低氧、饥饿的应激反应，如果自噬过度就可能导致自噬性死亡。我们预初实验发现：自噬性死亡可能与胞浆过度自噬、触发细胞核凋亡有关，是自噬与凋亡存在同一个细胞内，而此过程可能与HIF-1/p53表达水平的转变相关。. 因此，本课题在此工作基础上, 拟阐明：①增生性瘢痕中、重度缺血缺氧是诱导瘢痕成纤维细胞自噬和自噬性死亡的诱因。② HIF-1/P53转换是介导成纤维细胞自噬和自噬性死亡的关键途径，beclin-1是藕连细胞自噬和凋亡的枢纽。③证实靶向干预自噬，诱导成纤维细胞自噬性死亡，对增生性瘢痕具有治疗作用。课题结果拟阐明调控自噬性死亡的关键分子和途径，同时为靶向干预自噬治疗增生性瘢痕提供依据。

Previous studies revealed that there were media and severe ischemia in the proliferative and regressive scar tissue respectively , commitantly with autophagy and cell death happened, moreover, the expression of HIF-1 transited from high level to low level , but p53 expression increased to high level, meanwhile beclin-1 changed with HIF-1 .Autophagy is usually happened with hypoxia or starvation, so we assumed that under severe ischemia, it could cause excessive autophagy and induce cell death, which was mediated with low expression of HIF-1, and high P53. .On the base of previous findings, we would like to prove that the media and severe ischemia could induce the autophagy and cell death during scar progression. In addition , we established the model of hypoxia and starvation for cell culture ,and use siRNA to block expression of HIF-1,p53，beclin-1 respectively， to prove that HIF-1/p53 mediate the autophagy and cell death, and beclin-1 play a key role during this process. Furthermore ,we establish a model of hypertrophic scar in the rabbit ear, and apply rapamycin to the scar tissue to induce over-autophagy and then to investigate the scar volume and color, in order to explore the method of tageting autophagy for the scar treatment.