技巧主義 論爭에 대한 文學疏通理論的 硏究

학위논문(석사)--서울대학교 대학원 :국어교육과,1998.Maste

Compound C에 의한 지방세포 분화의 억제

학위논문(석사) --서울대학교 대학원 :약학과 약물학 전공,2008.8.Maste

(On)The Principle of text evaluation activity for poetry education

학위논문(박사)--서울대학교 대학원 :국어교육과 국어교육전공,2006.Docto

핵 수용체 RORα의 STAT3 신호전달과 간염증 조절 효과 규명

학위논문 (석사)-- 서울대학교 대학원 : 약학대학 약학과 병태생리학전공, 2016. 2. 이미옥.Chronic liver inflammation plays a critical role in various liver diseases. In an inflammatory region of liver, inflammtory cytokines, IL-6 and IL-22, constitutively activate signal transducer and activator of transcription 3 (STAT3) and exacerbate inflammation induced hepatocellular carcinoma. Therefore, Inhibition of STAT3 activity is important for regulation of liver malignancy. Retonoic acid receptor related orphan receptor α (RORα) is related various metabolism and inflammatory response. Recently, It is reported that RORα attenuates liver metabolic diseases, but it is unknown that RORα has relation with STAT3 activity. To investigate the relationship between RORα and STAT3 in liver inflammation, we used RORα overexpression adenovirus in primary mouse hepatocytes and HepG2 liver cancer cells. Our data showed that RORα overexpression decreased phosphorylation of STAT3 in liver cells. In contrast, RORα knockdown increased phosphorylation of STAT3. Moreover, we observed that RORα overexpression decreased STAT3 transcriptional activity. Synthetic RORα ligands, SR1078 and JC1-40, were also decreased STAT3 transcriptional activity. STAT3 downstream genes, myc and p53, expression was modulated when RORα was overexpressed in HepG2 cells. In order to find how RORα regulates STAT3 activity, we tested endogenous STAT3 regulators expression level when RORα is overexpressed in primary mouse hepatocytes. Four STAT3 regulators that are somatic mutated or downregulated in human cancers, were selected. Our data showed that RORα overexpression downregulated GRIM19 mRNA expression level in primary mouse hepatocytes. Next, we tested effects of RORα ligands in diethylnitrosamine-induced liver inflammation in vivo model. When RORα ligand, JC1-40, was treated, serum ALT and AST levels of mice were decreased and suppression of STAT3 phosphorylation was observed in mouse liver tissue. Infiltrated immune cells number were decreased when JC1-40 was administrated. Also, JC1-40 treatment reduced mRNA expression level of IL-1β and TNFα in liver tissue. In this study, we demonstrated that RORα regulates STAT3 activity by regulation of GRIM19 expression, and RORα ligand reduced STAT3 activity and inflammatory responses in diethylnitrosamine induced liver inflammation in vivo mice model. These findings revealed that RORα is a novel therapeutic target for inflammation-related liver diseases.Ⅰ.INTRODUCTION 1 Ⅱ.PURPOSE OF THE STUDY 7 Ⅲ.MATERIALS AND METHODS 8 1. Cell culture and cell treatment 8 2. Diethylnitrosamine-induced liver inflammation in vivo model 8 3. Recombinant adenovirus infection and siRNA transfection 9 4. Reporter gene assay 9 5. Wetern blot assay 10 6. Quantitative real-time polymerase chain reaction (qRT-PCR) 10 7. Statistic analysis 11 Ⅳ. RESULTS 14 1. RORα inhibits phosphorylation of STAT3 in liver cells 14 2. RORα suppresses the transcriptional activity of STAT3 14 3. RORα increases expression of STAT3 inhibitor, GRIM19 15 4. RORα reduces the diethylnitrosamine-induced inflammatory response and liver injury 16 Ⅴ. DISCUSSION 26 REFERENCES 29 국문초록 34Maste