서울대학교 생물정보학 협동과정과 생명과학부 공동주최로 특별 세미나를 아래와 같이 열고자 하오니, 많은 참여 바랍니다.

일시: 2015년 11월 11일 수요일 오전 11시

연사: Jun R. Huh (University of Massachusetts Medical School)

장소: 500동 목암홀

Title

Th17 cells: inflammatory immune cells promoting autoimmune diseases and neurodevelopmental disorders

Abstract

CD4+ T helper lymphocytes that secret interleukin-17 (Th17 cells) are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt. These cells have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. By performing a chemical screen with an insect cellbased reporter system, we previously identified and reported that the cardiac glycoside digoxin and its derivatives function as specific inhibitors of RORγt transcriptional activity. Digoxin inhibited Th17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. We also demonstrated that RORγt is important for the maintenance of IL-17 expression in mouse and human effector T cells. From a large-scale chemical screen covering more than 300,000 small molecules, we identified a second series of RORγt inhibitors. One compound (ML209) in this series exhibited lower than 100 nM IC50 in an in vitro RORγt competition assay. ML209 suppressed human Th17 cell differentiation at sub-micromolar concentrations.

In order to elucidate RORγt function in human cells by identifying the downstream targets of RORγt, deep-sequencing analyses were performed. We analyzed the gene expression profiles of human Th17 cells following treatment with two different RORγt inhibitors, the digoxin derivatives and ML209. Using these highly specific inhibitors, we have identified novel downstream targets of RORγt that play critical roles in human Th17 cells.

In addition, using a murine maternal immune activation (MIA) model and various genetic mutants targeting Th17 cells and RORγt pathways, we recently identified Th17 cells and the downstream IL-17 pathway involvement in maternal inflammation-induced

Education

1992-1996 Seoul National University, Seoul, Korea (Microbiology) B.S.

1996-1998 Seoul National University, Seoul, Korea (Advisor: Byeong Jae Lee) M.S.

1999-2005 California Institute of Technology, Pasadena, CA (Advisor: Bruce Hay) Ph.D.

Positions and Employment

1998-1999 Military duty, 32nd Army Division and National Assembly Library, South Korea

2005-2006 Postgraduate Research, Bruce A. Hay Laboratory, California Institute of Technology

2006-2013 Postdoctoral Fellow, Dan R. Littman Laboratory, New York University

2013-Present Assistant Professor, University of Massachusetts Medical School

Recent Publications

1. Sellars, M*., Huh, JR*., Day, K., Issuree, PD., Galan, C., Gobeil, S., Absher, D., Green, MR., Littman, DR. (2015) Regulation of DNA methylation dictates Cd4 gene expression during development of helper and cytotoxic T cells. Nature Immunology. Jul;16(7):746-54. PubMed PMID: 26030024; PubMed Central PMCID: PMC4474743. *Equally contributed.

2. Longman, RS., Diehl, GE., Victorio, D., Huh, JR., Galan, C., Miraldi E., Swaminath, A., Bonneau, R., Scherl, EJ., Littman, DR. (2014) CX3CR1+ Mononuclear Phagocytes Support Colitis-Associated Innate Lymphoid Cell Production of IL-22. Journal of Experimental Medicine. Jul 14. pii: jem.20140678.

3. Huh, JR., Englund, EE., Wang, H., Huang, H., Huang, P., Rastinejad, F., Inglese, J., Austin, CP., Johnson, RL., Huang, W., Littman, DR. (2013). Identification of Potent and Selective Diphenylpropanamide RORg Inhibitors. ACS Med Chem Lett. 4(1):79-84. PMCID: PMC3770298.

생물정보학 협동과정, 생명과학부 공동주최