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Graduate School of Ajou University
Department of Neuroscience and Technology Course
3. Theses(Master)
혈액에서 유입된 염증세포와 신호전달분자 Rac, SOCS에 의한 뇌염증반응의 조절에 관한 연구
- Alternative Title
- Kyung-Ae Ji
- Author(s)
- 지경애
- Alternative Author(s)
- Kyung-Ae Ji
- Advisor
- 조은혜
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2006-08
- Language
- eng
- Keyword
- brain inflammation
- Alternative Abstract
- Brain inflammation is a process of host defense against infection of injury. During this process, excessive inflammation could be harmful to surrounding tissue and consequently aggravate brain injury. Thus, to understand how brain inflammation occurs and how its duration and extent are controlled is important to limit neuronal damage in the brain. The first part of this thesis showed that activation of Rac1, a small G-protein, is involved in IFN-g-signaling in astrocytes. Compared to levels in control cells, IFN-g-induced GAS promoter activity and expressions of several IFN-g-responsive genes were markedly reduced in both cells expressing RacN17, a well-characterized Rac1 negative mutant. Thus, Rac1 may contribute to maximal activation of IFN-g responsive inflammatory signaling in rat astrocytes. The second part showed that thrombin, an inflammatory stimulator, increased expression of full name of cytokine-induced SH2 protein (CIS), one of SOCS family proteins. Since CIS reduced IFN-g-induced GAS-luciferase activity and tyrosine phosphorylation of STAT1 and STAT3, I concluded that thrombin could control duration and extent of inflammation by inducing expression of negative regulators of inflammation as well as pro-inflammatory mediators. In the third part, I showed regional differences in the extent of brain inflammation and neuronal damage in the substantia nigra pars compacta (SNpc) and the cortex, and underlying mechanisms that cause these differences. Microinjection of lipopolysaccharide (LPS) induced transient inflammatory responses and reversible neuronal damage in the cortex, but relatively severe and long-lasting inflammation and neuronal death in the SNpc. I found that the differential extent of neutrophil infiltration in these two areas could cause differential extent of inflammation. In the SNpc, cells labeled with two markers of microglia, OX-42 and ionized calcium binding adaptor molecule (Iba-1) showed different behaviors: The number of OX-42-ip cells increased at 12 h after LPS injection while the number of Iba-1-ip cells were dead. Since the OX-42 antibody detects CD11b that is expressed in neutrophils as well as in microglia, infiltration of neutrophils was detected using myeloperoxidase (MPO) as a specific marker of neutrophils. At 12 h following LPS injection, there was a dramatic increase in the number of MPO-ip neutrophils in the SNpc while relatively sparsely in the cortex. The MPO-ip cells were co-labeled with OX-42 and these cells expressed inducible nitric oxide synthase (iNOS). In agreement with these results, in leukopenic rats, MPO-ip cells were not detected for up to 3 days after LPS injection, and the loss of dopaminergic neurons were significantly attenuated. These results indicate that the extent of infiltrated neutrophil could determine the severity of inflammation in the cortex and the SNpc, and this event could be linked to the severity of neuronal damage in these two brain areas.
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