以下为第421次SKLBE 学术论坛信息,请阅。
报告题目:Finding Novel Anti-Tuberculosis Compounds
报告人:韩国明知大学 Prof. Joo-Won Suh (徐胄源)
时间:2018-6-20 14:00-15:30
地点:实验18楼315室
主持人:张立新教授
报告人简介
Prof. Joo-Won Suh (徐胄源)
2011-至今: 韩国21世纪绿色生物食医药素材开发事业项目团 团长
1990-至今 : 韩国明知大学 生命科学情报系 教授
1989-1990. : 美国威斯康辛大学(博士后)
1986-1989. : 美国加州大学戴维斯分校 (博士)
1984-1987. : 美国加州大学戴维斯分校 (硕士)
1972-1979. : 韩国首尔大学 ( 学士 )
徐胄源教授的研究方向聚焦在放线菌次级代谢产物的生物合成、菌种改良以及工业菌种的发酵工艺方面,迄今为止,共发表论文206篇 (其中SCI论文150篇,SCIE论文56篇) ,申请专利数量237项(注册86项),技术转让62个。
摘要
Finding Novel Anti-Tuberculosis Compounds
Tuberculosis (TB) has been known to be an infectious disease caused by Mycobacterium tuberculosis (M. tb) and still dangerous as 4,100 people have died per one day. Global incidence of TB is falling slowly because of first line anti-tuberculosis drug which combine ?isoniazid, ?rifampicin, pPyrazinamide and ?streptomycin. However, the MDR (multidrug resistant) and XDR (extensively drug resistant) TB incidence currently continue to increase globally. Therefore, the development of new anti-tuberculosis drugs is required for effective treatment of MDR and XDR TB.
In order to address this issue, we screened over 150,000 actinomycetes extracts through in vitro assay using M. tb resistant to existed drugs and isolated two anti-tuberculosis lead compounds as named to Ecumicin and rufomycin. Ecumicin and rufomycin are kind of cyclic peptides synthesized by NRPS (Non-Ribosomal Peptide Synthase) gene cluster of Nonomuraea sp. MJM3502 and Streptomyces atratus MJM3502 isolated from Korean soil, respectively. These compounds can kill MDR and XDR M. tuberculosis as well as drug susceptible M. tb and in vitro MIC of these compounds are comparable to recently developed drugs to treat MDR and XDR TB like bedaquiline and delamanid.
Through DARTS (Drug Affinity Responsive Target Stability) and mutation analysis, we discovered the mode of action that ecumicin and rufomycin as binding to ClpC1 that is an essential protein regulating protein homeostasis in M. tb. Even though both compounds bind ClpC1, ecumicin can kill M. tb resistant to rufomycin and vice versa. Interestingly, treatment of ecumicin stimulated ClpC1 ATPase activity but inhibited ClpC1/P1/P2 proteolytic activity. While, treatment of rufomycin only inhibited ClpC1/P1/P2 proteolytic activity. These results indicate that ecumicin and rufomycin bind to ClpC1 but the binding site of these compounds on ClpC1 are different. So, in order to figure out the binding site of ecumicin and rufomycin on ClpC1, we carried out X-ray crystallography and in silico docking simulation with N-terminal ClpC1. As a result, we identified that ecumicin binds to L92 and L96 but rufomycin binds to V13, H77 and F80 of ClpC1.
报告2:Mitophagy as a regulator of cardiac function in physiological and pathophysiological conditions
报 告 人:Dr. Nuo Sun
报告人:Ohio State University
时间:2018-6-20 15:30-17:00
地点:实验18楼315室
主持人:张立新教授
报告人简介
Dr. Sun is a tenure track Assistant Professor in the Department of physiology and Cell Biology at Ohio State University, and an Investigator at the Davis Heart & Lung Research Institute (DHLRI). He obtained his Ph.D. from Georgetown University, where he started to pursue research in mitochondrial biology. He received his postdoc training at the National Heart, Lung and Blood Institute (NHLBI), where he was able to develop a novel methodology to analyze and quantify in vivo mitophagy in a wide range of primary cells and tissues, and employ his system to analyze how mitophagy is altered under a host of varying environmental and genetic perturbations. The phenomenon of aging is an intrinsic feature of life. However, aging itself remains the greatest risk factor for all major life-threatening disorders, including Alzheimer's disease, Parkinson's disease, and cardiovascular disease. A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Dr. Sun has a great passion to investigate how mitochondria participate in aging, and to explore effective interventions to counteract aging and aging related diseases. His laboratory is focusing on mitochondrial functions and mitophagy in cardiac physiological and pathophysiological conditions. Using genome-scale CRISPR-Cas9 activation/repression screening and high-content image-based chemical screening, Nuo seeks to elucidate molecular pathways regulating mitophagy using cellular, genetic, and biochemical approaches. The laboratory work ranges from molecular biology to systems physiology using multiple genetically modified mouse models and iPSC technology.
报告摘要
Mitophagy as a regulator of cardiac function in physiological and pathophysiological conditions
A decline in mitochondrial quality has been associated with aging, neurodegenerative diseases and cardiovascular diseases. Mitophagy, a specialized autophagic pathway that mediates the lysosomal clearance of damaged mitochondria, is essential for mitochondrial quality control. Recent studies have demonstrated an important role for mitophagy in both developmental and disease-related metabolic transitioning of cardiac mitochondria. Thus, a better understanding of the physiological and pathological roles of cardiac mitophagy is critical for understanding the normal physiology of the heart, as well as potential spurring new potential treatments for a wide array of cardiovascular diseases.
Currently, our knowledge regarding mitophagy in the heart and the cardiomyocytes is limited. Establishing more reliable methods to monitor cardiac mitophagy would dramatically advance our understanding of the molecular signaling mechanisms of mitophagy. My studies provided the first robust assessment of in vivo mitophagy, and demonstrated that a transgenic mouse that expresses mt-Keima can provide direct in vivo measurements of cardiac mitophagic flux during both physiological and pathological conditions.
Furthermore, using genome-scale CRISPR-Cas9 activation/repression screening and high-content image-based chemical screening, I identified pathways/compounds that modulate mitophagy. In particular, accumulation of ubiquitinated outer mitochondrial membrane proteins has been proposed to act as a signal for selective mitophagy. However, removal of ubiquitin is achieved by the action of resident mitochondrial deubiquitinases, most notably USP30. Therefore, the USP30 knockout mice were generated to investigate whether genetic deletion of USP30 was able to stimulate cardiac mitophagy, and whether deletion/inhibition of USP30 could modulate disease progression in animal models of heart failure.