p53蛋白泛素化在翼状胬肉中的作用及发病机理研究

翼状胬肉是角膜缘上的结膜增生，患者可能出现视力模糊或双重视力。为了克服高复发，手术切除翼状胬肉时会用辅助疗法如丝裂霉素C（MMC）。但MMC的使用与多种并发症相关，而MMC本身属致癌物，因此有必要制定抑制翼状胬肉替代辅助疗法。我们之前发现MMC除了杀死翼状胬肉细胞，还会明显杀死结膜细胞 。另我们发现p53蛋白泛素化抑制剂Nutlin却可针对杀死翼状胬肉细胞而只对结膜细胞有轻微影响。这些结果说明p53蛋白泛素化在翼状胬肉发病机理有重要影响。p53是最被广泛研究和是诱导细胞衰老和凋亡以限制癌症生长最重要的蛋白。我们想找出翼状胬肉细胞中p53被泛素化的赖氨酸残基。通过定点诱变将翼状胬肉细胞中的p53这些赖氨酸突变成精氨酸，使p53不能被泛素化，从而分析这情况下翼状胬肉细胞的生理反应。这项研究将提高我们对p53被泛素化引致翼状胬肉发病机理的认识。预期研究结果有助未来设计针对翼状胬肉的专属治疗手段。

Pterygium is a triangular-shaped hyperplastic growth of the bulbar conjunctiva over the limbus. If the pterygium tissues cover the cornea, patients may suffer from blurry vision or double vision. To overcome the high recurrence, adjunct therapies including Mitomycin C (MMC) has been developed. However, the use of MMC has been reported to associate with multiple complications. And MMC has been classified as a carcinogen. Therefore it is important to develop alternative adjunct therapies in suppressing pterygium. Our previous studies found that the p53 ubiquitylation inhibitor Nutlin could kill pterygium cells specifically with minimal effects on conjunctiva cells. These findings illustrate the importance of p53 ubiquitylation in the pathogenesis of pterygium. p53 is a well-studied protein which can induce senescence and apoptosis to restrict the growth of cancer. In this study, we aim to identify the p53 lysine residues that are ubiquitylated in pterygium. We will then mutate these lysine residues into arginine to prevent p53 ubiquitylation in pterygium cells and to investigate the cellular responses of these cells. This study will understand the roles of p53 ubiquitylation in the pathogenesis of pterygium. Results from this study will help to develop specific treatments for pterygium.