基于红细胞膜疟原虫诱生阴离子通道(PSAC)的青蒿素类药物抗疟机理研究

Artemisinin, discovered by Chinese scientists in the early 1970s, is an effective antimalarial drug with low toxicity. Although intensive efforts have been devoted to explore the mode of action of this class of drugs, its exact mechanism remains an enigma. Many hypotheses have been proposed, such as iron and heme model, mitochondria model, PfATP6 model, and so forth. Recent studies have demonstrated that .malaria infected erythrocytes show increased permeability to a number of ions and various nutrient solutes important for parasite growth as mediated by the Plasmodial Surface Anion Channel (PSAC). We hypothesize that antimalarial action of artemisinins on parasite growth and proliferation is performed through inhibiting clag3-induced PSAC activity..My previous study showed that Dihydroartemisinin (DHA) possess potent inhibitory activities on parasite viability: Here，to investigate the effects of artemisinins on the main ion channel、PSAC channel activity and the P.falciparum clag3 gene of iRBC membrane, this project apply the relevant experimental techniques such as whole-cell patch-clamp configuration and gene silencing and switched etc. The study propose to identify the mechanisms of antimalarial action that allow artemisinins to exert its dual benefit through PSAC, further to illuminate the relationship between PSAC channel activity and the main ion channel activity of erythrocyte membrane, to provide a mechanistic overview of the action of artemisinins. I hope these findings provide a useful starting point for deciphering mechanisms of antimalarial action of artemisinins in the malaria infected erythrocyte.

青蒿素抗疟极其高效，但青蒿素类药物抗疟活性及作用机制至今尚不明确，而围绕青蒿素抗疟机制又有较多的学说理论，提示青蒿素类药物可能通过多种机制发挥抗疟作用，新近发现和证实的疟原虫感染红细胞（iRBC）膜疟原虫诱生阴离子通道（PSAC）是疟原虫发育增殖的关键营养汲取通道，提示或许青蒿素类药物有可能通过影响PSAC活性，阻碍疟原虫在红细胞内的发育增殖，从而发挥抗疟作用。.申请人前期研究表明，双氢青蒿素（DHA）有可能影响体外培养疟原虫寄生的红细胞膜物质渗透性，本项目主要采用膜片钳和基因沉默等相关实验技术，研究青蒿素类药物对iRBC膜主要离子通道、PSAC通道活性的影响，及研究青蒿素类药物对PSAC关键疟原虫编码基因clag3的影响，探讨基于iRBC膜PSAC的青蒿素类药物抗疟机理，以及阐明PSAC通道活性变化与红细胞膜主要离子通道活性变化的关系，为青蒿素抗疟机制阐释和更好利用提供实验依据。

青蒿素抗疟极其高效，但青蒿素类药物抗疟活性及作用机制至今尚不明确，而围绕青蒿素抗疟机制又有较多的学说理论，提示青蒿素类药物可能通过多种机制发挥抗疟作用，深入探讨其抗疟机制不仅可以加深对药物的认识，而且对于指导临床合理用药、防止抗药株的产生、发现新的青蒿素抗疟组合、拓宽临床应用等都有重要意义。本项目在国家自然科学基金委的支持下，基于青蒿素类化合物选择性作用于红内期疟原虫的特点，首先聚焦于青蒿素类化合物与疟原虫感染红细胞的相互作用开展工作。通过对青蒿素类化合物影响染虫红细胞膜诱生阴离子通道（PSAC）及其他主要离子通道活性解析、初步研究青蒿素类药物（双氢青蒿素DHA/青蒿琥酯ART）对PSAC关键疟原虫编码基因clag3的影响。课题实施过程中，明确3D7感染前后，红细胞膜主要离子通道活性变化、红细胞膜PSAC通道活性特征；DHA/ART对感染红细胞的生长和疟原虫体内发育增殖的影响，及主要离子通道的影响；阐述DHA与PSAC、编码基因clag3之间的相互影响关系，力图在基于iRBC膜PSAC的青蒿素类药物抗疟机理研究方面有所发现、有所突破。通过项目实施，旨在夯实研究基础，培育可持续研究方向，为青蒿素抗疟机制阐释和更好利用提供实验依据。