臺灣博碩士論文加值系統

OSMR 是 IL-6 細胞激素成員 OSM 的主要接受器，而 OSMR 所活化的下游路徑為 JAK/STAT 以及 MAPK 路徑，此路徑可刺激許多種類的細胞激素以及發炎物質表現。 GADD45a 為屬於 GADD45 蛋白質家族成員之一， GADD45a 可以被一些環境因子例如 UV light 、藥物等刺激而產生。相關研究更指出 GADD45a 會促進細胞的去甲基化作用，某些報告也說明 epigenetic mechanisms 被認為與 RA 之致病機轉有關聯性。此研究想了解 OSMR 以及 GADD45a SNPs 基因型變化以及 PBMC 中其 mRNA 表現量與 RA 以及 SLE 之間的關聯性。
此研究挑選 RA 、 SLE 病人，以及作為實驗對照組之正常人族群，抽取周邊周邊血液單核球之 total RNA 以及全血之 genomic DNA ，觀察 OSMR 和 GADD45a 基因表現以及基因型分析與 RA 和 SLE 是否有關連性。
結果顯示 OSMR mRNA 在 RA 以及 SLE 病患的 PBMC 中均無表達，但其啟動子區域 -100G>T 位置在 SLE 病人若帶有 T allele ，可能與 SLE 的致病有關。而 GADD45a 結果顯示在 PBMC 中其 mRNA 在 RA 以及 SLE 病患表現比起正常族群有偏高現象，而且在 SLE 族群此偏高現象是具有統計上的差異。觀察 GADD45a 表現量，發現在 RA 病患中，其表現量越高，則發炎臨床指標 ESR 以及 CRP 也有上升的現象。此研究為初步觀察 OSMR 和 GADD45a 基因表現以及基因型分析與 RA 和 SLE 是否有關連性，未來可以在更深入研究，了解 OSMR 和 GADD45a 對於自體免疫疾病所扮演之角色。

OSMR is the main receptor for OSM, one of the IL-6 cytokine family.OSMR activated JAK / STAT and MAPK pathway and this pathway can stimulate the production of many of the class of cytokines and inflammatory substances. GADD45a is member of the GADD45 protein family,Some environmental factors such as UV light, drugs can stimulate GADD45a production.More research show that GADD45a protein will promote demethylation, the report also shows certain epigenetic mechanisms are considered to be the pathogenesis of RA. This study want to understand the relationship between OSMR and GADD45a with RA and SLE.
This research enroll RA, SLE patients, and normal cases.Taking total RNA of the peripheral blood monocytes and genomic DNA of whole blood cells for study.Observe the gene expression and SNP genotyping of GADD45a and OSMR with RA,SLE and normal cases.
This study showed that OSMR mRNA in RA and SLE patients had no expression in PBMC, but if the promoter region -100G> T position in SLE patients taken T allele,it may be may be a risk factor for the development of SLE. The expression of GADD45a mRNA in PBMC of RA and SLE patients with elevated level, and the expression of GADD45a mRNA in PBMC of SLE patients have statistical differences.The higher amount of GADD45a expression in RA patients, the higher the amount of ESR and CRP level .This study is a preliminary observation about OSMR and GADD45a gene expression and SNP genotyping with RA and SLE. It is important to understand the detail of OSMR and GADD45a in onset of autoimmune diseases in future times.

中文摘要 2
英文摘要 3
縮寫檢索表 5
前言 6
研究目的 12
實驗材料與方法 13
結果 19
討論 24
參考文獻 27
附表 31
附圖 55

1.Choy, E.H. and G.S. Panayi, Cytokine pathways and joint inflammation in rheumatoid arthritis. The New England journal of medicine, 2001. 344(12): p. 907-16.
2.Cross, A., et al., Secretion of oncostatin M by neutrophils in rheumatoid arthritis. Arthritis and rheumatism, 2004. 50(5): p. 1430-6.
3.Hui, W., M. Bell, and G. Carroll, Detection of oncostatin M in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis, 1997. 56(3): p. 184-7.
4.Robak, E., et al., Circulating interleukin-6 type cytokines in patients with systemic lupus erythematosus. European cytokine network, 1997. 8(3): p. 281-6.
5.Heinrich, P.C., et al., Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical journal, 2003. 374(Pt 1): p. 1-20.
6.Zhang, Q., et al., Structures and biological functions of IL-31 and IL-31 receptors. Cytokine & growth factor reviews, 2008. 19(5-6): p. 347-56.
7.Liebermann, D.A. and B. Hoffman, Gadd45 in stress signaling. Journal of molecular signaling, 2008. 3: p. 15.
8.Barreto, G., et al., Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature, 2007. 445(7128): p. 671-5.
9.Ma, D.K., et al., DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation. Cell cycle, 2009. 8(10): p. 1526-31.
10.Sen, G.L., et al., DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature, 2010. 463(7280): p. 563-7.
11.Strickland, F.M. and B.C. Richardson, Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity, 2008. 41(4): p. 278-86.
12.Schmitz, K.M., et al., TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation. Molecular cell, 2009. 33(3): p. 344-53.
13.van der Pouw Kraan, T.C., et al., Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis and rheumatism, 2003. 48(8): p. 2132-45.
14.Samal, B., et al., Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Molecular and cellular biology, 1994. 14(2): p. 1431-7.
15.Jia, S.H., et al., Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. The Journal of clinical investigation, 2004. 113(9): p. 1318-27.
16.Ognjanovic, S., et al., Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes. Journal of molecular endocrinology, 2001. 26(2): p. 107-17.
17.Ognjanovic, S. and G.D. Bryant-Greenwood, Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes. American journal of obstetrics and gynecology, 2002. 187(4): p. 1051-8.
18.Patrone, L., et al., Genes expressed during the IFN[gamma]-induced maturation of pre-B cells. Molecular immunology, 2002. 38(8): p. 597-606.
19.Xu, L.G., et al., Identification of downstream genes up-regulated by the tumor necrosis factor family member TALL-1. Journal of leukocyte biology, 2002. 72(2): p. 410-6.
20.Nowell, M.A., et al., Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis and rheumatism, 2006. 54(7): p. 2084-95.
21.Liu, C.C., et al., Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunology letters, 2011. 135(1-2): p. 96-9.
22.Li, Y., et al., Overexpression of the growth arrest and DNA damage-induced 45alpha gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis and rheumatism, 2010. 62(5): p. 1438-47.
23.Lu, Q., A. Wu, and B.C. Richardson, Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. Journal of immunology, 2005. 174(10): p. 6212-9.
24.Lu, Q., et al., Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis and rheumatism, 2002. 46(5): p. 1282-91.
25.Kaplan, M.J., et al., Demethylation of Promoter Regulatory Elements Contributes to Perforin Overexpression in CD4+ Lupus T Cells. The Journal of Immunology, 2004. 172(6): p. 3652-3661.
26.Oelke, K., et al., Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis and rheumatism, 2004. 50(6): p. 1850-60.
27.Lu, Q., et al., Demethylation of CD40LG on the inactive X in T cells from women with lupus. Journal of immunology, 2007. 179(9): p. 6352-8.