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研究生:楊登超
研究生(外文):Deng-Chao Yang
論文名稱:利用可疏水性轉換之螢光標定蛋白水解酵素基質探針以非侵犯性造影活體腸道發炎疾病
論文名稱(外文):Noninvasive imaging of Inflammatory bowel by hydrophobic conversion of a fluorescent protease substrate
指導教授:莊國祥莊國祥引用關係
指導教授(外文):Kuo- hsiang Chuang
口試委員:李美賢鄭添祿
口試委員(外文):Mei- Hsien LeeTian-Lu Cheng
口試日期:2015-12-14
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:生藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:38
中文關鍵詞:發炎性腸道疾病;基質金屬蛋白酶-2
外文關鍵詞:Inflammatory bowel disease;Matrix metalloproteinase-2
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腸道發炎疾病(Inflammatory bowel disease, IBD)是國人近年來的通病,嚴重者可能造成腸穿孔,一旦發現此類疾病,不易治癒會反覆發作。過去開發治療IBD的藥物常利用IBD小鼠動物模型去評估治療藥物的療效但往往需要大量的實驗老鼠、花費大量的金錢和消耗大量的時間來得到結果,對於藥物的開發極於曠日費時。為了解決上述問題,本實驗我們以IBD發生時基質金屬蛋白酶-2 (Matrix metalloproteinase-2 , MMP-2)表現量會增加的現象,利用已經成功開發出的PEG- MMP-2 peptide-TMR進行各項活體內外的測試,從體外試驗可觀察出此造影劑可經由IBD發生時常見的白血球浸潤及刺激纖維母細胞的情形會表現大量活化態MMP-2而後對此造影劑進行水解並累積於發炎區域,在活體內試驗也可得到具有腸道發炎的老鼠組別有較強的螢光累積情形,並對腸道發炎組織和參與腸道發炎相關細胞進行活化態MMP-2 蛋白質測定,結果顯示腸道發炎情形會提高活化態MMP-2 蛋白質表現量,藉此可以利用本實驗結果應用於IBD藥物的開發,此造影劑可連續且即時偵測老鼠腸道組織的恢復情或發炎的情況,經由螢光累積特性快速且確實的推論出治療藥物的功效,大幅減少實驗鼠與金錢的花費,加速藥物的開發。
Inflammatory bowel disease (Inflammatory bowel disease, IBD) is a common problem for people in recent years and severe cases may cause intestinal perforation. Once people get IBD, it is difficult to cure and have recurrent trouble easily. In order to develop therapeutic drugs of IBD, IBD animal model is often used to evaluate the efficacy of therapeutic drugs in the past, but it often requires a lot of experimental mice, spend a lot of money and consume a lot of time to get experimental results that will be time consuming. In order to solve these problems, we have shown that the expression of activated MMP-2 in IBD animal model was increased. The PEG- MMP-2 peptide-TMR has been successfully developed in vivo and in vitro experiments. When IBD occurs, Leukocyte infiltrates and stimulates fibroblast cells to produce large numbers of activated MMP-2 form in vitro. Then hydrolysis of PEG- MMP-2 peptide-TMR by MMP2 and accumulated in the inflamed area. IBD animal model group has a strong fluorescence accumulation in vivo. Activated MMP-2 protein is measured for inflammatory bowel tissue and intestinal inflammation associated cells. The results showed that the intestinal inflammation situation will increase the amount of activated MMP-2 protein expression. We can take advantage of the experimental results applied to the development of IBD drugs. This PEG- MMP-2 peptide-TMR can continuously and immediately detect the recovery situation or Inflammatory conditions of intestinal tissue of mice. Fast and reliably infer the efficacy of the therapeutic agent by accumulations of PEG- MMP-2 peptide-TMR. Finally, accelerate the development of drugs by reducing the cost of money and only a few mice.
目 錄
第一章、緒論…..……………………………….………1.
第二章、研究材料與方法………………………………4.
第三章、結果……………………………………………9.
第四章、討論………………………….……………….12.
第五章、圖表………………………….……………….15.
第六章、參考文獻……………………………….…….22.
第七章、附錄………………………….……………….28.
1.Molodecky, N.A., et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46-54.e42; quiz e30 (2012).
2.Jakobovits, S.L. & Travis, S.P. Management of acute severe colitis. British medical bulletin 75-76, 131-144 (2005).
3.Jarnerot, G., et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 128, 1805-1811 (2005).
4.Melgar, S., et al. Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease. International immunopharmacology 8, 836-844 (2008).
5.Kullberg, M.C., et al. Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infection and immunity 69, 4232-4241 (2001).
6.Powrie, F., et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553-562 (1994).
7.Scheinin, T., Butler, D.M., Salway, F., Scallon, B. & Feldmann, M. Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis. Clinical and experimental immunology 133, 38-43 (2003).
8.Totsuka, T., et al. Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis. American journal of physiology. Gastrointestinal and liver physiology 284, G595-603 (2003).
9.Campbell, S., Travis, S. & Jewell, D. Ciclosporin use in acute ulcerative colitis: a long-term experience. European journal of gastroenterology & hepatology 17, 79-84 (2005).
10.Murthy, S.N., et al. Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin. Digestive diseases and sciences 38, 1722-1734 (1993).
11.Soriano-Izquierdo, A., et al. Effect of cyclosporin A on cell adhesion molecules and leukocyte-endothelial cell interactions in experimental colitis. Inflammatory bowel diseases 10, 789-800 (2004).
12.Garg, P., et al. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. American journal of physiology. Gastrointestinal and liver physiology 296, G175-184 (2009).
13.Lone, B.A. & Department of Biotechnology, U.o.K., Srinagar, J&K, India. MMP-9, MMP-2 Profile in Different Mice Tissues and LPS Induced MMP-9 and MMP-2 Expression in RAW 264.7 Cells, Down Regulated by Emodin Treatment International Journal of Interdisciplinary and Multidisciplinary Studies 1, 1-7 (2014).
14.Han, Y.P., Tuan, T.L., Wu, H., Hughes, M. & Garner, W.L. TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP. Journal of cell science 114, 131-139 (2001).
15.Hayden, D.M., Forsyth, C. & Keshavarzian, A. The role of matrix metalloproteinases in intestinal epithelial wound healing during normal and inflammatory states. The Journal of surgical research 168, 315-324 (2011).
16.Maxwell, J.R., Brown, W.A., Smith, C.L., Byrne, F.R. & Viney, J.L. Methods of inducing inflammatory bowel disease in mice. Current protocols in pharmacology / editorial board, S.J. Enna (editor-in-chief) ... [et al.] Chapter 5, Unit5.58 (2009).
17.Wirtz, S., Neufert, C., Weigmann, B. & Neurath, M.F. Chemically induced mouse models of intestinal inflammation. Nature protocols 2, 541-546 (2007).
18.Okayasu, I., et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694-702 (1990).
19.Boismenu, R. & Chen, Y. Insights from mouse models of colitis. Journal of leukocyte biology 67, 267-278 (2000).
20.Bolzani, G., Della Coletta, R., Martelli Junior, H., Martelli Junior, H. & Graner, E. Cyclosporin A inhibits production and activity of matrix metalloproteinases by gingival fibroblasts. Journal of periodontal research 35, 51-58 (2000).
21.Silva, H.C., et al. The effect of cyclosporin A on the activity of matrix metalloproteinases during the healing of rat molar extraction wounds. Archives of oral biology 46, 875-879 (2001).
22.Chiu, H.C., et al. Cyclosporine A inhibits the expression of membrane type-I matrix metalloproteinase in gingiva. Journal of periodontal research 44, 338-347 (2009).
23.Sukkar, T.Z., et al. Gingival fibroblasts grown from cyclosporin-treated patients show a reduced production of matrix metalloproteinase-1 (MMP-1) compared with normal gingival fibroblasts, and cyclosporin down-regulates the production of MMP-1 stimulated by pro-inflammatory cytokines. Journal of periodontal research 42, 580-588 (2007).
24.Gagliano, N., et al. Effect of cyclosporin A on human gingival fibroblast collagen turnover in relation to the development of gingival overgrowth: an in vitro study. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 58, 231-238 (2004).
25.Kincaid, R.L., Takayama, H., Billingsley, M.L. & Sitkovsky, M.V. Differential expression of calmodulin-binding proteins in B, T lymphocytes and thymocytes. Nature 330, 176-178 (1987).
26.Harrison, C.A., Bastan, R., Peirce, M.J., Munday, M.R. & Peachell, P.T. Role of calcineurin in the regulation of human lung mast cell and basophil function by cyclosporine and FK506. British journal of pharmacology 150, 509-518 (2007).
27.Kountouras, J., Zavos, C. & Chatzopoulos, D. Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease. Journal of cellular and molecular medicine 8, 317-328 (2004).
28.Chuang, C.H., et al. In vivo positron emission tomography imaging of protease activity by generation of a hydrophobic product from a noninhibitory protease substrate. Clinical cancer research : an official journal of the American Association for Cancer Research 18, 238-247 (2012).
29.Kirkegaard, T., Pedersen, G., Saermark, T. & Brynskov, J. Tumour necrosis factor-alpha converting enzyme (TACE) activity in human colonic epithelial cells. Clinical and experimental immunology 135, 146-153 (2004).
30.Bailey, C.J., et al. Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn''s disease and normal intestine. Journal of clinical pathology 47, 113-116 (1994).
31.von Lampe, B., Barthel, B., Coupland, S.E., Riecken, E.O. & Rosewicz, S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47, 63-73 (2000).
32.Stallmach, A., et al. Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 47, 415-422 (2000).
33.Baugh, M.D., et al. Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117, 814-822 (1999).
34.Herias, M.V., Koninkx, J.F., Vos, J.G., Huis in''t Veld, J.H. & van Dijk, J.E. Probiotic effects of Lactobacillus casei on DSS-induced ulcerative colitis in mice. International journal of food microbiology 103, 143-155 (2005).
35.Liotta, L.A., Steeg, P.S. & Stetler-Stevenson, W.G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64, 327-336 (1991).
36.Nagase, H. & Woessner, J.F., Jr. Matrix metalloproteinases. The Journal of biological chemistry 274, 21491-21494 (1999).
37.McCawley, L.J. & Matrisian, L.M. Matrix metalloproteinases: they''re not just for matrix anymore! Current opinion in cell biology 13, 534-540 (2001).
38.Heimesaat, M.M., et al. The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)10 ameliorates acute DSS colitis. European journal of microbiology & immunology 2, 192-200 (2012).
39.Rath, T., et al. Presence of intestinal Mycobacterium avium subspecies paratuberculosis (MAP) DNA is not associated with altered MMP expression in ulcerative colitis. BMC gastroenterology 11, 34 (2011).
40.M''Koma, A.E. Inflammatory bowel disease: an expanding global health problem. Clinical medicine insights. Gastroenterology 6, 33-47 (2013).
41.Hahm, K.B., et al. Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49, 190-198 (2001).
42.Macintyre, I.M. Best practice in groin hernia repair. The British journal of surgery 90, 131-132 (2003).
43.Conze, J., Klinge, U. & Schumpelick, V. [Incisional hernia]. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 76, 897-909; quiz 910 (2005).
44.Rosch, R., et al. Biomaterial-dependent MMP-2 expression in fibroblasts from patients with recurrent incisional hernias. Hernia : the journal of hernias and abdominal wall surgery 10, 125-130 (2006).
45.Forbes, S.S., Eskicioglu, C., McLeod, R.S. & Okrainec, A. Meta-analysis of randomized controlled trials comparing open and laparoscopic ventral and incisional hernia repair with mesh. The British journal of surgery 96, 851-858 (2009).
46.Xiong, W., Meisinger, T., Knispel, R., Worth, J.M. & Baxter, B.T. MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome. Circulation research 110, e92-e101 (2012).
47.Wilkinson, J.M., et al. MMP-14 and MMP-2 are key metalloproteases in Dupuytren''s disease fibroblast-mediated contraction. Biochimica et biophysica acta 1822, 897-905 (2012).
48.Ma, X., et al. Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP-13 expression. Biochimica et biophysica acta 1852, 1038-1048 (2015).
49.Tsung, A.J., et al. Downregulation of matrix metalloproteinase-2 (MMP-2) utilizing adenovirus-mediated transfer of small interfering RNA (siRNA) in a novel spinal metastatic melanoma model. International journal of oncology 32, 557-564 (2008).
50.Correction: olmesartan decreased levels of IL-1beta and TNF-alpha, down-regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model. PloS one 10, e0120057 (2015).
51.Han, X., et al. GHGKHKNK octapeptide (P-5m) inhibits metastasis of HCCLM3 cell lines via regulation of MMP-2 expression in in vitro and in vivo studies. Molecules (Basel, Switzerland) 17, 1357-1372 (2012).
52.Mosig, R.A., et al. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Human molecular genetics 16, 1113-1123 (2007).
53.Barnett, J.M., et al. Pharmacologic and genetic manipulation of MMP-2 and -9 affects retinal neovascularization in rodent models of OIR. Investigative ophthalmology & visual science 48, 907-915 (2007).
54.Williams, T.M., et al. Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. The Journal of biological chemistry 279, 51630-51646 (2004).
55.Neurath, M.F., et al. Noninvasive assessment of Crohn''s disease activity: a comparison of 18F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte scintigraphy with labeled antibodies. The American journal of gastroenterology 97, 1978-1985 (2002).
56.Das, C.J., et al. PET-CT enteroclysis: a new technique for evaluation of inflammatory diseases of the intestine. European journal of nuclear medicine and molecular imaging 34, 2106-2114 (2007).
57.Louis, E., et al. Noninvasive assessment of Crohn''s disease intestinal lesions with (18)F-FDG PET/CT. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 48, 1053-1059 (2007).
58.Wood, K.A., Hoskin, P.J. & Saunders, M.I. Positron emission tomography in oncology: a review. Clinical oncology (Royal College of Radiologists (Great Britain)) 19, 237-255 (2007).
59.Jacene, H.A., et al. Prediction of the need for surgical intervention in obstructive Crohn''s disease by 18F-FDG PET/CT. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 50, 1751-1759 (2009).
60.Spier, B.J., Perlman, S.B. & Reichelderfer, M. FDG-PET in inflammatory bowel disease. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the So 53, 64-71 (2009).
61.Ahmadi, A., et al. Diagnostic value of noninvasive combined fluorine-18 labeled fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography enterography in active Crohn''s disease. Inflammatory bowel diseases 16, 974-981 (2010).
62.Lobert, P., et al. Spectrum of physiological and pathological cardiac and pericardial uptake of FDG in oncology PET-CT. Clinical radiology 68, e59-71 (2013).
63.Wu, Y., et al. Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients. International journal of cancer. Journal international du cancer 132, E37-47 (2013).
64.Dambha, F., Tanner, J. & Carroll, N. Diagnostic imaging in Crohn''s disease: what is the new gold standard? Best practice & research. Clinical gastroenterology 28, 421-436 (2014).
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