酪氨酸激酶FAK1对新生儿脓毒症相关的血管内皮炎症反应的调控机制研究

新生儿脓毒症(NS)是由致病菌及感染因素造成的全身性炎症反应。如果得不到及时治疗，可导致器官功能障碍，是一种新生儿期的危重症。目前，对NS病理生理学机制的研究还很缺乏，其发病机理也远未阐明，值得深入研究。血管内皮细胞促炎激活是NS关键的病理变化，也是诱发器官损伤的重要环节。研究表明，蛋白激酶调节内皮细胞超炎症反应，与脓毒症病情进展密切相关。预实验结果发现粘着斑激酶1(FAK1)在内皮细胞受到促炎细胞因子刺激后磷酸化激活，抑制其活化可显著降低内皮炎症反应。由此，我们推测酪氨酸激酶FAK1通过促进内皮细胞炎症反应，进而参与调控脓毒症引发的内皮以及器官功能损伤。本课题拟结合激酶组学、分子生物学、免疫学等手段，分别在细胞水平，动物模型和临床样本三个层面深入研究FAK1在NS中的临床意义和分子调控机理。研究结果将为NS的早期控制和治疗提供有益的科学依据和新的策略。

Neonatal sepsis (NS) is a systemic inflammatory response to a severe infection caused by pathogens. It is a critical illness for neonates with high morbidity and mortality, frequently leading to organ dysfunction. Nowadays, the study on the pathophysiological mechanisms of neonatal sepsis is still scarce, and the precise pathogenesis of organ dysfunction is also not completely elucidated yet. Previous studies have described pro-inflammatory activation of vascular endothelial cells is an important pathological change in neonatal sepsis, and it is also a major contributor to sepsis-induced organ failure. Recent studies have shown that protein kinases, which regulates the endothelial hyper-inflammatory responses of endothelial cells, play a critical role in the development of sepsis. Our preliminary results demonstrate that focal adhesion kinase 1 (FAK1) is activated by pro-inflammatory cytokines in endothelial cells, and the inhibition of FAK1 activation significantly reduces endothelial inflammatory responses. Therefore, we speculate that the protein kinase FAK1 is actively involved in the regulation of sepsis-related endothelium and organ dysfunction via promoting the inflammatory response of endothelial cells. Using phosphoproteomic to examine kinase activity, molecular biology and immunology, we aim to investigate the clinical significance and regulatory mechanisms of FAK1 in neonatal sepsis in vitro and in vivo. These results will provide sufficient scientific basis and new strategies for the treatment of neonatal sepsis.