腺苷/HIF-1α通路调控红系祖细胞代谢重编程促应激红系造血的作用及机制研究

Stress erythropoiesis is an effective type of erythrocyte generation in response to stress stimulus. Although it had greatly potential in clinic, the application of stress erythropoiesis is limited due to the shortage of understanding the underlying mechanism. By conducting high-altitude human trials and genetic mice study, we showed for the first time that elevated plasma adenosine activates ADORA2B receptor anchored in the cytomembrane of erythroid progenitor cell (HPC), and subsequently promote stress erythropoiesis. The preliminary results from high-profile metabolomics revealed that activated adenosine ADORA2B signaling promotes uptake of glucose and glutamine, causing a metabolic reprogramming of HPC, and finally contributes to stress erythropoiesis. Based on our previous works and literature, we proposed a novel hypothesis that hypoxia-inducible factor 1  (HIF-1α) underlies adenosine erythroid ADORA2B signaling-mediated metabolic reprogramming of HPC by regulation of glucose transporter (Glut1/Glut4) and glucose transporter (ASCT2), promoting stress erythropoiesis. To test our hypothesis, ChIP analysis and RNA-seq in purified erythroids will be utilized. Meanwhile, specific agonists targeting on ADORA2B or HIF-1α will be utilized to assess their potential to boost stress erythropoiesis. Moreover, we will explore the role of adenosine signaling in two independent clinical relevant stress erythropoiesis mice models. This study will reveal novel mechanism underlying stress erythropoiesis, contribute to its clinical application and provide novel therapeutic strategy to treat erythropoiesis disordered.

应激红系造血是一种高效的红系生成方式，但因其调控机制不明而临床应用受限。申请人前期高原人体试验和动物研究证明：缺氧环境下，升高的血浆腺苷可通过结合红系祖细胞膜上ADORA2B受体进而促进应激红系造血。前期预实验结果提示：活化的腺苷通路可通过增加红系祖细胞对葡萄糖和谷氨酰胺的摄取，调控红系祖细胞代谢重编程以刺激应激红系造血。本项目提出科学假说：腺苷通路通过作用于红系祖细胞内的核心靶点HIF-1α，转录调控葡萄糖和谷氨酰胺转运体的表达，进而调控代谢重编程，推动应激红系造血。本研究拟运用ChIP和RNA-Seq等技术深度挖掘HIF-1α诱导红系祖细胞代谢重编程的作用及其分子机制；探明ADORA2B和HIF-1α靶向激活剂促进应激红系造血的作用；探究在临床相关红系造血疾病模型中腺苷通路的应用潜力。本研究将为造血调控分子网络的完善、应激红系造血的临床转化提供基础。

应激红系造血是一种高效的红系生成方式，但因其调控机制不明而临床应用受限。在国家自然科学基金的资助下，我们在腺苷/HIF-1α通路调控红系祖细胞代谢重编程促应激红系造血的作用及临床应用潜力方面取得了重要进展，并进一步揭示了腺苷信号通路在肿瘤微环境中作用及机制，相关成果发表在Cancer Cell等国际权威杂志，其中有3 篇文章 IF>10.0，最高IF=31.743 共计8篇。同时，后续获得了国家优秀青年基金、国家科技部政府间重点研发项目等资助。