Full metadata record
DC Field | Value | Language |
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dc.contributor.advisor | 정영해 | - |
dc.contributor.author | 이윤옥 | - |
dc.creator | 이윤옥 | - |
dc.date.accessioned | 2016-08-25T10:08:00Z | - |
dc.date.available | 2016-08-25T10:08:00Z | - |
dc.date.issued | 2010 | - |
dc.identifier.other | OAK-000000060622 | - |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/185930 | - |
dc.identifier.uri | http://dcollection.ewha.ac.kr/jsp/common/DcLoOrgPer.jsp?sItemId=000000060622 | - |
dc.description.abstract | Pathogenesis of neuroinflammatory/neurodegenerative diseases, including Alzheimer’s disease (AD) and human immunodeficiency virus type 1 (HIV-1) associated dementia (HAD) is associated Glutamate or HIV-1 Tat protein with the upregulation of a number of chemokines, such as monocyte chemotactic protein-1 (MCP-1)/chemokine (C-C motif) lignad 2 (CCL2). In this study, we assessed the potential molecular basis for the role of glutamate or HIV-1 Tat in hippocampal inflammation by determining its effects on MCP-1 induction. We also attempted to identify the mechanism by which resveratrol (trans-3, 5, 4'-trihydroxystilbene), a polyphenolic phytostilbene, modulates the expression of MCP-1 in the glutamate- or HIV-1 Tat-stimulated hippocampus. An ex vivo study using rat hippocampal slices demonstrated a time- and dose-dependent increase in MCP-1 release from glutamate- or HIV-1 Tat-exposed rat hippocampus. This increase was accompanied by enhanced MCP-1 production via the activation of the ERK pathway and production of IL-1β or TNF-α, were also induced in response to glutamate or HIV-1 Tat respectively, expression. The inhibition of the ERK pathway with SL327, which is capable of crossing the blood-brain barrier, nearly abolished the observed glutamate- or HIV-1 Tat-induced effects. It is worthy of note that resveratrol, to a similar degree as SL327, down-regulated glutamate- or HIV-1 Tat-induced IL-1β or TNF-α respectively expression and reduced the expression of MCP-1 production via the inactivation of ERK1/2. These results indicate that the activation of the ERK pathway and the consequent production of IL-1β or TNF-α expression are essential for glutamate- or HIV-1 Tat-stimulated MCP-1 production in the rat hippocampus. Additionally, our data reveal an anti-inflammatory mechanism of resveratrol involving the inactivation of the ERK1/2 pathway in the rat hippocampus, which is linked principally to HAD-associated cognitive dysfunction.;글루타민산염이나 후천성면역결핍증 (HIV-1) Tat 단백질은 알츠하이머병과 HIV-1 관련 치매와 같은 신경염증/신경퇴행성 질환의 병인과 관련하여 단핵세포 주화성 단백질(MCP-1)과 같은 케모카인의 발현을 유도한다. 본 논문에서는 글루타민산염이나 HIV-1 Tat에 의한 MCP-1의 유도에 따른 백서 해마에서의 염증작용의 분자학적 기전을 규명하였다. 또한 폴리페놀의 일종인 레스베라트롤이 백서 해마에서 글루타민산염이나 HIV-1 Tat 에 의한 MCP-1의 발현을 조절하는 기전을 증명하였다. 백서 해마를 생체 밖으로 꺼내서 실험하는 방법을 이용하여 해마에서 글루타민산염이나 HIV-1 Tat에 의하여 MCP-1의 생산이 유도되는 것을 관찰하였다. 이 경우 MCP-1의 생산은 ERK 경로의 활성화에 따라 나타나는 염증 유도 사이토카인인 IL-1β나 TNF-α의 발현이 함께 일어나는 것이 관찰되었다. ERK 경로를 억제하는 SL327에 의해 글루타민산염이나 HIV-1 Tat에 의한 MCP-1의 생산이 억제되었다. SL327과 유사하게, 레스베라트롤에 의해서도 글루타민산염이나 HIV-1 Tat에 의한 ERK경로의 활성화가 줄어들면서 염증 유도 사이토카인의 생산과 MCP-1의 생산이 억제되었다. 이와 같은 실험 결과를 종합해 볼 때 백서 해마에서 글루타민산염이나 HIV-1 Tat에 의한 MCP-1의 생산에는 ERK 경로의 활성화 되며 IL-1β나 TNF-α의 생산이 이루어지고 그에 따라 MCP-1의 생산이 이루어진다는 가능성을 제시한다. 더불어, 백서 해마에서 레스베라트롤은 ERK 경로를 불활성화시킴으로써 항염증작용이 나타낸다는 것을 시사한다. | - |
dc.description.tableofcontents | I. Introduction 1 II. Materials and Methods 6 A. Materials 6 B. Hippocampal slice cultures 7 C. Experimental treatment 8 D. Resveratrol Treatment 9 E. Lactate Dehydrogenase Activity 9 F. Enzyme-Linked Immunoabsorbant Assay (ELISA) 10 G. Polyacrylamide Gel Electrophoresis and Western Blotting 10 H. Quantitative RT-PCR 11 I. Statistical Analysis 12 III. Results 14 A. Glutamate induced MCP-1 secretion and MCP-1 mRNA accumulation 14 B. Glutamate-induced MCP-1 gene expression requires ERK1/2 MAPK activation 15 C. Evidence for the role of endogenous IL-1 in glutamate-induced MCP-1 production 17 D. HIV-1 Tat 1-86 induced MCP-1 production 18 E. HIV-1 Tat 1-86-induced MCP-1 production requires ERK1/2 MAPK activation 19 F. Evidences for the role of endogenous TNF-α in HIV-1 Tat 1-86-induced MCP-1 production 20 G. Resveratrol inhibits glutamate-induced changes of MCP-1 production via inhibition of glutamate-induced ERK 1/2 activation and IL-1β production 22 H. Resveratrol inhibits HIV-1 Tat 1-86-induced changes of MCP-1 production via inhibition HIV-1 Tat 1-86-induced ERK 1/2 activation and TNF-α production 23 IV. Discussion 36 V. Reference 47 국문 초록 58 | - |
dc.format | application/pdf | - |
dc.format.extent | 2050331 bytes | - |
dc.language | eng | - |
dc.publisher | 이화여자대학교 대학원 | - |
dc.title | Glutamate or HIV-1 Tat protein induced MCP-1 production via activation of ERK1/2 pathway in rat hippocampal slice cultures | - |
dc.type | Doctoral Thesis | - |
dc.title.subtitle | inhibition by resveratrol | - |
dc.format.page | viii, 59 p. | - |
dc.identifier.thesisdegree | Doctor | - |
dc.identifier.major | 대학원 의과학과 | - |
dc.date.awarded | 2010. 8 | - |