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활성 산소 조절을 통한 TLR 신호 전달 매개 염증 치료에 대한 연구

Title
활성 산소 조절을 통한 TLR 신호 전달 매개 염증 치료에 대한 연구
Other Titles
The Study of ROS Regulation as a Therapeutic Target to TLR-mediated Inflammation
Author
김예람
Advisor(s)
양철수
Issue Date
2019. 8
Publisher
한양대학교
Degree
Doctor
Abstract
Reactive oxygen species (ROS) are essential factors of innate immune systems, but un-controlled inflammation triggered by oxidative stress is the cause of many inflammatory diseases. Especially, superoxide generation from NADPH oxidase (NOX) plays important roles in killing microbes in professional phagocytes. However, the exact regulation of this process remains unclear. In this dissertation, I demonstrate that negative regulators of cellular ROS generation from NOX are effective strategies against Toll-like receptor (TLR)-mediated inflammatory responses. In the first experiment, I show that the novel role of c-Src in cellular ROS generation through its binding to p47phox. c-Src inhibits the NOX complex assembly. Furthermore, I developed the c-Src-SH3 peptide conjugated with schizophyllan (SPG), which is a β-1,3-glucan. The SPG-SH3 peptide effectively inhibits NOX complex assembly and proinflammatory response in TLR stimulation. In mouse ROS-mediated diseases, the SPG-SH3 has a protective effect. In the second experiment, I demonstrate the role of N8 peptide in ROS-mediated inflammatory responses. N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, can block p22phox-Rubicon interaction, that is an essential interaction for ROS production. Furthermore, I developed N8 peptide-mimetic small molecules, compound 1 and 2, through in silico virtual screening and structure modification. These molecules can block p22phox-Rubicon interaction and reduce inflammatory responses. Consequently, treatment with these molecules showed protective effects in acute inflammatory models, sepsis and colitis, and chronic inflammatory model, rheumatoid arthritis. Therefore, these negative regulators are potential therapeutic agents for ROS-related inflammatory responses. For this reason, regulating ROS is a significant target for controlling the inflammatory response.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000109621http://repository.hanyang.ac.kr/handle/20.500.11754/109836
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIONANOTECHNOLOGY(바이오나노학과) > Theses (Ph.D.)
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