标题：A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

摘要：Artemisinins are the cornerstone of anti-malarial drugs.Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K),revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparumKelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

报告人：张翠（袁晶老师实验室）

课程指导老师：莫玮教授

时间：2015年12月30日 周三下午 4：30

地点：生命科学学院五楼学术报告厅

标题：Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

摘要：The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (D/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulatorIl18bpresulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued inIl18bp/;Il18r D/EC mice,demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells.IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis.

报告人：杨典强（杨云清老师实验室）

课程指导老师：袁晶教授

时间：2015年12月30日 周三下午 4：30

地点：生命科学学院五楼学术报告厅

标题：MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response

摘要：MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murineTLR7and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor–immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.

报告人：ABDUL GHAFOOR（杨云清老师实验室）

课程指导老师：黄烯教授

时间：2015年12月30日 周三下午 4：30

地点：生命科学学院五楼学术报告厅