Kindlin-2 在肺纤维化发展中作用的研究

CRITICAL ROLES OF KINDLIN-2 IN THE PROGRESSION OF PULMONARY FIBROSIS

张萍

11849371

硕士

生物学

郭玲

2020-06-05

2020-07-08

哈尔滨工业大学

深圳

肺纤维化是一种进行性和致命性的肺部疾病，其特征是肺成纤维细胞的活化和细胞外基质蛋白如胶原蛋白的过度沉积。我们发现在肺纤维化患者的肺组织中，kindlin-2 及其结合蛋白PYCR1 的表达水平显著升高，其中PYCR1 是一种脯氨酸合成的关键酶。利用TGF-β1 处理人肺成纤维细胞，会显著增加细胞中kindlin-2 和PYCR1 的表达，进而提高kindlin-2-PYCR1 复合物的形成和脯氨酸的合成。吡非尼酮是一种经临床批准的治疗肺纤维化的药物，可显著降低kindlin-2-PYCR1 复合物的形成和脯氨酸的合成。此外，在人肺成纤维细胞中仅敲除kindlin-2 足以抑制TGF-β1 诱导的PYCR1 表达增加，脯氨酸合成和成纤维细胞的活化。最后，利用博莱霉素诱导的肺纤维化小鼠模型，我们发现在体内敲除kindlin-2 可以有效降低PYCR1、脯氨酸和胶原基质的表达水平，减轻肺纤维化的发展。我们的研究结果表明，kindlin-2 是一种肺成纤维细胞活化、胶原基质合成和肺纤维化的关键促进因子，强调了针对kindlin-2 信号通路治疗这种致命性肺部疾病的潜力。

Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the levels of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-β1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased formation of the kindlin-2-PYCR1 complex and proline synthesis. The levels of the kindlin-2-PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone, a clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-β1-induced increases of PYCR1 expression, proline synthesis and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the levels of PYCR1, proline and collagen matrix and alleviate the progression of pulmonary fibrosis in vivo. Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease.

肺纤维化 kindlin-2 PYCR1 TGF-β1

pulmonary fibrosis kindlin-2 PYCR1 TGF-β1

中文

联合培养

南方科技大学

张萍. Kindlin-2 在肺纤维化发展中作用的研究[D]. 深圳. 哈尔滨工业大学,2020.