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시스템생물학적인 접근방법을 통한 세포독성 및 세포신호전달의 기능적 분석
- Alternative Title
- Choi Yong-Min
- Author(s)
- Choi, Yong Min
- Alternative Author(s)
- Choi Yong-Min
- Advisor
- 최상돈
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2014-08
- Language
- eng
- Alternative Abstract
- In recent years, much research has been carried out to develop novel drugs to treat diseases, however, we are in the need to develop drugs that have least side effects, maximum efficacy and appropriate drug tolerance. Inside a body, drugs perform their biological actions and excrete out through the kidney. The blood flow is higher in the kidney in comparison to other tissues, and due to a toxic nature of various substances, they damage the kidney. Particularly, some drugs can potentially cause renal cytotoxicity, therefore, it is pivotal to elucidate the underlying mechanism of how renal cytotoxicity is perpetuated. The first part of this study unveiled the mechanism of cisplatin-induced renal toxicity, an anticancer drug used to treat various cancers. Chemotherapeutic use of cisplatin is limited by its severe side effects. Here, by analyzing different omics data (transcriptome, metabolome and proteome), we demonstrated the cisplatin-induced cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. The foremost reason of cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways, resulting in the collapse of mitochondrial energy production, which sensitized the cells to death. The quenching of ROS led to the amelioration of affected pathways. Considering these observations, a significant correlation between cisplatin and metabolic dysfunctions was concluded involving mROS as the major player. The second part of this study dealt the elucidation of toxicity studies of cyclosporin A (CsA). CsA is a calcineurin inhibitor, and is widely used to treat organ transplantation associated complexities but its use is limited due to renal dysfunction. We performed expression analysis using microarray in CsA treated HK-2 cells, and found that ER stress-related genes and apoptosis inducing genes are evidently expressed. Furthermore, we found an inverse relation in ATF3, a stress and apoptosis regulatory gene, and CHOP, an apoptosis inducing protein, expression level. When ATF3 knock down cells were exposed to CsA, CHOP is induced that stimulated ROS production, destabilized the membrane potential of the mitochondria and triggered cell death. These results established that CsA induced-cytotoxicity increased in ATF3 lacking cells as compared to wild type. Taken together, our data demonstrated that ATF3 play a pivotal role in preventing CsA-induced cytotoxicity by inhibiting ER stress-mediated ROS production. Cumulatively, these findings enhance the understanding of renal toxicity mechanisms, furnished new targets to alleviate cytotoxicity, and it could be used in preliminary data for drug development.
- Fulltext
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- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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