缺氧和炎症是影响高原病的发生和发展的两个关键因素，而这两种因素之间的相互作用机制仍然知之甚少。已知，HIF-1能够正向调控IL-1β释放，但其潜在机制仍然不清楚。此外，HIF-1的活性是否受到IL-1β的反馈调节尚缺乏研究。本课题组前期工作显示，L-天冬酰胺（L-Asn）能够显著促进IL-1β的释放。此外，L-Asn是FIH抑制HIF-1活性的作用位点，我们假设L-Asn作为竞争性作用底物，减弱FIH对HIF-1活性的抑制作用。由此推测，在缺氧条件下，L-Asn介导的HIF活性增强所形成的前馈环能够超敏化炎症小体信号通路。本课题拟采用分子和细胞生物学，探索L-Asn促进炎症小体活化的潜在机制，和L-Asn能否介导HIF-1活化增强；并通过数学建模，定量地分析前馈环于炎症小体超敏性活化的作用。本课题的研究对阐明HIF-1和炎症小体的相互作用机制具有重要的意义，为防治高原病提供新的靶点和策略。

Hypoxia and inflammation are two key factors affecting the occurrence and development of acute high altitude disease (such as high altitude pulmonary edema) and chronic high altitude disease (such as high altitude pulmonary hypertension). However, the interaction mechanism between these two factors is still poorly understood. It has been reported that the HIF-1 contributes to macrophage production of IL-1β, but the underlying mechanism remains unclear. In addition, whether the activity of HIF-1 is regulated by IL-1β is still lack of scientific research. The preliminary work of our group showed that the L-Asparagine (L-Asn), as an important intermediate of glucose metabolism, can significantly promote the activation of NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, and increase the expression and release of IL-1β. In addition, the L-Asn as a site of inhibition of HIF-1 activity by FIH, we hypothesized that the L-Asn acts as a competitive substrate to attenuate the inhibitory effect of FIH on HIF-1 activity. Hence, it is speculated that under hypoxic conditions, the feedforward loop generated by L-Asn-mediated HIF-1 activation can hypersensitize the inflammasome signaling. This study intends to adopt molecular and cellular biology to explore the potential mechanisms by which L-Asn promotes inflammasome activation, and whether L-Asn can mediate HIF-1 activation to form a feedforward loop; and to employ mathematical model to systematically and quantitatively analyze the function of feedforward loop generated by L-Asn-mediated HIF-1 activation on ultrasensitivity of inflammasome signaling. Our study has important significance for elucidating the interaction mechanism between HIF-1 and inflammasomes, and provides new targets and strategies for the prevention and treatment of acute and chronic high altitude diseases.