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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陶秘華(Mi-Hua Tao) | |
| dc.contributor.author | Yao-Ming Shih | en |
| dc.contributor.author | 石燿茗 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:45:45Z | - |
| dc.date.available | 2021-02-26 | |
| dc.date.copyright | 2016-02-26 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-11-30 | |
| dc.identifier.citation | 1. Seeger, C, Zoulim, F and Mason, WS (2007). Hepadanavirus. In: Fields, BN, Knipe, DM and Howley, PM (eds) Fields Virology, 5th edn Wolters Kluwer Health/Lippincott Williams & Wilkins: Philadelphia.
2. Schaefer, S (2007). Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J Gastroenterol 13: 14-21. 3. Fung, SK, and Lok, AS (2004). Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? Hepatology 40: 790-792. 4. Shuping Tong, JL, Jack R Wands and Yu-mei Wen (2013). Hepatitis B virus genetic variants: biological properties and clinical implications. Emerging Microbes & Infections 2: e10. 5. Henry Lik-Yuen Chan, VW-SW (2012). Chapter 30 – Hepatitis B. Zakim and Boyer's Hepatology (Sixth Edition): 540-563. 6. Loffler-Mary, H, Dumortier, J, Klentsch-Zimmer, C, and Prange, R (2000). Hepatitis B virus assembly is sensitive to changes in the cytosolic S loop of the envelope proteins. Virology 270: 358-367. 7. Tron, F, Degos, F, Brechot, C, Courouce, AM, Goudeau, A, Marie, FN, et al. (1989). Randomized dose range study of a recombinant hepatitis B vaccine produced in mammalian cells and containing the S and PreS2 sequences. J Infect Dis 160: 199-204. 8. Urban, S, and Gripon, P (2002). Inhibition of duck hepatitis B virus infection by a myristoylated pre-S peptide of the large viral surface protein. J Virol 76: 1986-1990. 9. Bruss, V, and Vieluf, K (1995). Functions of the internal pre-S domain of the large surface protein in hepatitis B virus particle morphogenesis. J Virol 69: 6652-6657. 10. Le Seyec, J, Chouteau, P, Cannie, I, Guguen-Guillouzo, C, and Gripon, P (1999). Infection process of the hepatitis B virus depends on the presence of a defined sequence in the pre-S1 domain. J Virol 73: 2052-2057. 11. Birnbaum, F, and Nassal, M (1990). Hepatitis B virus nucleocapsid assembly: primary structure requirements in the core protein. J Virol 64: 3319-3330. 12. Porterfield, JZ, Dhason, MS, Loeb, DD, Nassal, M, Stray, SJ, and Zlotnick, A (2010). Full-length hepatitis B virus core protein packages viral and heterologous RNA with similarly high levels of cooperativity. J Virol 84: 7174-7184. 13. Hadziyannis, SJ, and Vassilopoulos, D (2001). Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 34: 617-624. 14. Visvanathan, K, Skinner, NA, Thompson, AJ, Riordan, SM, Sozzi, V, Edwards, R, et al. (2007). Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45: 102-110. 15. Milich, D, and Liang, TJ (2003). Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38: 1075-1086. 16. Chisari, FV (2000). Rous-Whipple Award Lecture. Viruses, immunity, and cancer: lessons from hepatitis B. Am J Pathol 156: 1117-1132. 17. Chotiyaputta, W, and Lok, AS (2009). Hepatitis B virus variants. Nat Rev Gastroenterol Hepatol 6: 453-462. 18. Feitelson, MA, Reis, HM, Liu, J, Lian, Z, and Pan, J (2005). Hepatitis B virus X antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis. Front Biosci 10: 1558-1572. 19. Bouchard, MJ, and Schneider, RJ (2004). The enigmatic X gene of hepatitis B virus. J Virol 78: 12725-12734. 20. Xu, Z, Yen, TS, Wu, L, Madden, CR, Tan, W, Slagle, BL, et al. (2002). Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J Virol 76: 2579-2584. 21. Yan, H, Zhong, G, Xu, G, He, W, Jing, Z, Gao, Z, et al. (2012). Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1: e00049. 22. Newbold, JE, Xin, H, Tencza, M, Sherman, G, Dean, J, Bowden, S, et al. (1995). The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes. J Virol 69: 3350-3357. 23. Tuttleman, JS, Pourcel, C, and Summers, J (1986). Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 47: 451-460. 24. Zhang, YY, Zhang, BH, Theele, D, Litwin, S, Toll, E, and Summers, J (2003). Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver. Proc Natl Acad Sci U S A 100: 12372-12377. 25. Rehermann, B, and Nascimbeni, M (2005). Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5: 215-229. 26. Kremsdorf, D, Soussan, P, Paterlini-Brechot, P, and Brechot, C (2006). Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene 25: 3823-3833. 27. Kwon, H, and Lok, AS (2011). Hepatitis B therapy. Nat Rev Gastroenterol Hepatol 8: 275-284. 28. Chen, CJ, Yang, HI, Su, J, Jen, CL, You, SL, Lu, SN, et al. (2006). Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295: 65-73. 29. Tseng, TC, Liu, CJ, Yang, HC, Su, TH, Wang, CC, Chen, CL, et al. (2013). Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 57: 441-450. 30. Tseng, TC, Liu, CJ, Yang, HC, Su, TH, Wang, CC, Chen, CL, et al. (2012). High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 142: 1140-1149 e1143; quiz e1113-1144. 31. Chen, MT, Billaud, JN, Sallberg, M, Guidotti, LG, Chisari, FV, Jones, J, et al. (2004). A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A 101: 14913-14918. 32. Yang, HI, Lu, SN, Liaw, YF, You, SL, Sun, CA, Wang, LY, et al. (2002). Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 347: 168-174. 33. Gao, B, Duan, Z, Xu, W, and Xiong, S (2009). Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain. Hepatology 50: 424-433. 34. Li, N, Zhang, L, Chen, L, Feng, W, Xu, Y, Chen, F, et al. (2012). MxA inhibits hepatitis B virus replication by interaction with hepatitis B core antigen. Hepatology 56: 803-811. 35. Kim, JH, Luo, JK, and Zhang, DE (2008). The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression. J Immunol 181: 6467-6472. 36. Park, IH, Baek, KW, Cho, EY, and Ahn, BY (2011). PKR-dependent mechanisms of interferon-alpha for inhibiting hepatitis B virus replication. Mol Cells 32: 167-172. 37. Lau, GK, Piratvisuth, T, Luo, KX, Marcellin, P, Thongsawat, S, Cooksley, G, et al. (2005). Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 352: 2682-2695. 38. Janssen, HL, van Zonneveld, M, Senturk, H, Zeuzem, S, Akarca, US, Cakaloglu, Y, et al. (2005). Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365: 123-129. 39. Marcellin, P, Lau, GK, Bonino, F, Farci, P, Hadziyannis, S, Jin, R, et al. (2004). Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 351: 1206-1217. 40. Hoofnagle, JH, Di Bisceglie, AM, Waggoner, JG, and Park, Y (1993). Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 104: 1116-1121. 41. Buster, EH, Hansen, BE, Buti, M, Delwaide, J, Niederau, C, Michielsen, PP, et al. (2007). Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology 46: 388-394. 42. Chang, TT, Gish, RG, de Man, R, Gadano, A, Sollano, J, Chao, YC, et al. (2006). A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 354: 1001-1010. 43. Lai, CL, Chien, RN, Leung, NW, Chang, TT, Guan, R, Tai, DI, et al. (1998). A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 339: 61-68. 44. Lai, CL, Gane, E, Liaw, YF, Hsu, CW, Thongsawat, S, Wang, Y, et al. (2007). Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357: 2576-2588. 45. Marcellin, P, Chang, TT, Lim, SG, Tong, MJ, Sievert, W, Shiffman, ML, et al. (2003). Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348: 808-816. 46. Marcellin, P, Heathcote, EJ, Buti, M, Gane, E, de Man, RA, Krastev, Z, et al. (2008). Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 359: 2442-2455. 47. Hadziyannis, SJ, Tassopoulos, NC, Heathcote, EJ, Chang, TT, Kitis, G, Rizzetto, M, et al. (2003). Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 348: 800-807. 48. Lai, CL, Shouval, D, Lok, AS, Chang, TT, Cheinquer, H, Goodman, Z, et al. (2006). Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 354: 1011-1020. 49. Tassopoulos, NC, Volpes, R, Pastore, G, Heathcote, J, Buti, M, Goldin, RD, et al. (1999). Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 29: 889-896. 50. Warner, N, and Locarnini, S (2008). The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology 48: 88-98. 51. Villet, S, Pichoud, C, Billioud, G, Barraud, L, Durantel, S, Trepo, C, et al. (2008). Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol 48: 747-755. 52. Lee, YS, Suh, DJ, Lim, YS, Jung, SW, Kim, KM, Lee, HC, et al. (2006). Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 43: 1385-1391. 53. Kitrinos, KM, Corsa, A, Liu, Y, Flaherty, J, Snow-Lampart, A, Marcellin, P, et al. (2014). No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology 59: 434-442. 54. Reignat, S, Webster, GJ, Brown, D, Ogg, GS, King, A, Seneviratne, SL, et al. (2002). Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J Exp Med 195: 1089-1101. 55. Wu, L, and Belasco, JG (2008). Let me count the ways: mechanisms of gene regulation by miRNAs and siRNAs. Mol Cell 29: 1-7. 56. Kim, VN, Han, J, and Siomi, MC (2009). Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10: 126-139. 57. Martinez, J, Patkaniowska, A, Urlaub, H, Luhrmann, R, and Tuschl, T (2002). Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110: 563-574. 58. Frank, F, Sonenberg, N, and Nagar, B (2010). Structural basis for 5'-nucleotide base-specific recognition of guide RNA by human AGO2. Nature 465: 818-822. 59. Meister, G, Landthaler, M, Patkaniowska, A, Dorsett, Y, Teng, G, and Tuschl, T (2004). Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 15: 185-197. 60. Aravin, AA, Lagos-Quintana, M, Yalcin, A, Zavolan, M, Marks, D, Snyder, B, et al. (2003). The small RNA profile during Drosophila melanogaster development. Dev Cell 5: 337-350. 61. Tam, OH, Aravin, AA, Stein, P, Girard, A, Murchison, EP, Cheloufi, S, et al. (2008). Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453: 534-538. 62. Watanabe, T, Totoki, Y, Toyoda, A, Kaneda, M, Kuramochi-Miyagawa, S, Obata, Y, et al. (2008). Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453: 539-543. 63. Waterhouse, PM, Wang, MB, and Lough, T (2001). Gene silencing as an adaptive defence against viruses. Nature 411: 834-842. 64. Elbashir, SM, Harborth, J, Lendeckel, W, Yalcin, A, Weber, K, and Tuschl, T (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494-498. 65. Davidson, BL, and McCray, PB, Jr. (2011). Current prospects for RNA interference-based therapies. Nat Rev Genet 12: 329-340. 66. Gitlin, L, Stone, JK, and Andino, R (2005). Poliovirus escape from RNA interference: short interfering RNA-target recognition and implications for therapeutic approaches. J Virol 79: 1027-1035. 67. Boden, D, Pusch, O, Lee, F, Tucker, L, and Ramratnam, B (2003). Human immunodeficiency virus type 1 escape from RNA interference. J Virol 77: 11531-11535. 68. Kapadia, SB, Brideau-Andersen, A, and Chisari, FV (2003). Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci U S A 100: 2014-2018. 69. Palliser, D, Chowdhury, D, Wang, QY, Lee, SJ, Bronson, RT, Knipe, DM, et al. (2006). An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 439: 89-94. 70. Ge, Q, Filip, L, Bai, A, Nguyen, T, Eisen, HN, and Chen, J (2004). Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc Natl Acad Sci U S A 101: 8676-8681. 71. An, DS, Qin, FX, Auyeung, VC, Mao, SH, Kung, SK, Baltimore, D, et al. (2006). Optimization and functional effects of stable short hairpin RNA expression in primary human lymphocytes via lentiviral vectors. Mol Ther 14: 494-504. 72. McCaffrey, AP, Nakai, H, Pandey, K, Huang, Z, Salazar, FH, Xu, H, et al. (2003). Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 21: 639-644. 73. Morrissey, DV, Lockridge, JA, Shaw, L, Blanchard, K, Jensen, K, Breen, W, et al. (2005). Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23: 1002-1007. 74. Uprichard, SL, Boyd, B, Althage, A, and Chisari, FV (2005). Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci U S A 102: 773-778. 75. Chen, CC, Ko, TM, Ma, HI, Wu, HL, Xiao, X, Li, J, et al. (2007). Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA. Gene Ther 14: 11-19. 76. Wooddell, CI, Rozema, DB, Hossbach, M, John, M, Hamilton, HL, Chu, Q, et al. (2013). Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection. Mol Ther 21: 973-985. 77. Chen, CC, Sun, CP, Ma, HI, Fang, CC, Wu, PY, Xiao, X, et al. (2009). Comparative study of anti-hepatitis B virus RNA interference by double-stranded adeno-associated virus serotypes 7, 8, and 9. Mol Ther 17: 352-359. 78. Robbins, M, Judge, A, Liang, L, McClintock, K, Yaworski, E, and MacLachlan, I (2007). 2'-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther 15: 1663-1669. 79. Wheeler, LA, Trifonova, R, Vrbanac, V, Basar, E, McKernan, S, Xu, Z, et al. (2011). Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest 121: 2401-2412. 80. Pieken, WA, Olsen, DB, Benseler, F, Aurup, H, and Eckstein, F (1991). Kinetic characterization of ribonuclease-resistant 2'-modified hammerhead ribozymes. Science 253: 314-317. 81. Kumar, P, Ban, HS, Kim, SS, Wu, H, Pearson, T, Greiner, DL, et al. (2008). T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134: 577-586. 82. Kumar, P, Wu, H, McBride, JL, Jung, KE, Kim, MH, Davidson, BL, et al. (2007). Transvascular delivery of small interfering RNA to the central nervous system. Nature 448: 39-43. 83. Kawasaki, AM, Casper, MD, Freier, SM, Lesnik, EA, Zounes, MC, Cummins, LL, et al. (1993). Uniformly modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J Med Chem 36: 831-841. 84. Guo, P, Coban, O, Snead, NM, Trebley, J, Hoeprich, S, Guo, S, et al. (2010). Engineering RNA for targeted siRNA delivery and medical application. Adv Drug Deliv Rev 62: 650-666. 85. Zhang, S, Zhi, D, and Huang, L (2012). Lipid-based vectors for siRNA delivery. J Drug Target 20: 724-735. 86. Rose, JK, Buonocore, L, and Whitt, MA (1991). A new cationic liposome reagent mediating nearly quantitative transfection of animal cells. Biotechniques 10: 520-525. 87. Kanasty, R, Dorkin, JR, Vegas, A, and Anderson, D (2013). Delivery materials for siRNA therapeutics. Nat Mater 12: 967-977. 88. Hu-Lieskovan, S, Heidel, JD, Bartlett, DW, Davis, ME, and Triche, TJ (2005). Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res 65: 8984-8992. 89. Heilbronn, R, and Weger, S (2010). Viral vectors for gene transfer: current status of gene therapeutics. Handb Exp Pharmacol: 143-170. 90. Deng, Y, Wang, CC, Choy, KW, Du, Q, Chen, J, Wang, Q, et al. (2014). Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene 538: 217-227. 91. Suhy, DA, Kao, SC, Mao, T, Whiteley, L, Denise, H, Souberbielle, B, et al. (2012). Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model. Mol Ther 20: 1737-1749. 92. Borel, F, Kay, MA, and Mueller, C (2014). Recombinant AAV as a platform for translating the therapeutic potential of RNA interference. Mol Ther 22: 692-701. 93. Couto, LB, and High, KA (2010). Viral vector-mediated RNA interference. Curr Opin Pharmacol 10: 534-542. 94. Manche, L, Green, SR, Schmedt, C, and Mathews, MB (1992). Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol Cell Biol 12: 5238-5248. 95. Kim, DH, Longo, M, Han, Y, Lundberg, P, Cantin, E, and Rossi, JJ (2004). Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase. Nat Biotechnol 22: 321-325. 96. Marques, JT, Devosse, T, Wang, D, Zamanian-Daryoush, M, Serbinowski, P, Hartmann, R, et al. (2006). A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol 24: 559-565. 97. Judge, AD, Sood, V, Shaw, JR, Fang, D, McClintock, K, and MacLachlan, I (2005). Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 23: 457-462. 98. Judge, AD, Bola, G, Lee, AC, and MacLachlan, I (2006). Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13: 494-505. 99. Grimm, D, Streetz, KL, Jopling, CL, Storm, TA, Pandey, K, Davis, CR, et al. (2006). Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441: 537-541. 100. Jackson, AL, Burchard, J, Schelter, J, Chau, BN, Cleary, M, Lim, L, et al. (2006). Widespread siRNA 'off-target' transcript silencing mediated by seed region sequence complementarity. RNA 12: 1179-1187. 101. Birmingham, A, Anderson, EM, Reynolds, A, Ilsley-Tyree, D, Leake, D, Fedorov, Y, et al. (2006). 3' UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods 3: 199-204. 102. Ui-Tei, K, Naito, Y, Nishi, K, Juni, A, and Saigo, K (2008). Thermodynamic stability and Watson-Crick base pairing in the seed duplex are major determinants of the efficiency of the siRNA-based off-target effect. Nucleic Acids Res 36: 7100-7109. 103. Gu, S, Zhang, Y, Jin, L, Huang, Y, Zhang, F, Bassik, MC, et al. (2014). Weak base pairing in both seed and 3' regions reduces RNAi off-targets and enhances si/shRNA designs. Nucleic Acids Res. 104. Wu, HL, Huang, LR, Huang, CC, Lai, HL, Liu, CJ, Huang, YT, et al. (2005). RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant. Gastroenterology 128: 708-716. 105. Chandra, PK, Kundu, AK, Hazari, S, Chandra, S, Bao, L, Ooms, T, et al. (2012). Inhibition of Hepatitis C Virus Replication by Intracellular Delivery of Multiple siRNAs by Nanosomes. Mol Ther 20: 1724-1736. 106. ter Brake, O, Konstantinova, P, Ceylan, M, and Berkhout, B (2006). Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther 14: 883-892. 107. Weinberg, MS, Ely, A, Barichievy, S, Crowther, C, Mufamadi, S, Carmona, S, et al. (2007). Specific inhibition of HBV replication in vitro and in vivo with expressed long hairpin RNA. Mol Ther 15: 534-541. 108. Hoggan, MD, Blacklow, NR, and Rowe, WP (1966). Studies of small DNA viruses found in various adenovirus preparations: physical, biological, and immunological characteristics. Proc Natl Acad Sci U S A 55: 1467-1474. 109. Muzyczka, N (1992). Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 158: 97-129. 110. Sonntag, F, Schmidt, K, and Kleinschmidt, JA (2010). A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc Natl Acad Sci U S A 107: 10220-10225. 111. Cecchini, S, Negrete, A, and Kotin, RM (2008). Toward exascale production of recombinant adeno-associated virus for gene transfer applications. Gene Ther 15: 823-830. 112. Buller, RM, and Rose, JA (1978). Characterization of adenovirus-associated virus-induced polypeptides in KB cells. J Virol 25: 331-338. 113. Kotin, RM, Siniscalco, M, Samulski, RJ, Zhu, XD, Hunter, L, Laughlin, CA, et al. (1990). Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A 87: 2211-2215. 114. Kotin, RM, Menninger, JC, Ward, DC, and Berns, KI (1991). Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics 10: 831-834. 115. Kotin, RM, Linden, RM, and Berns, KI (1992). Characterization of a preferred site on human chromosome 19q for integration of adeno-associated virus DNA by non-homologous recombination. EMBO J 11: 5071-5078. 116. Xiao, W, Chirmule, N, Berta, SC, McCullough, B, Gao, G, and Wilson, JM (1999). Gene therapy vectors based on adeno-associated virus type 1. J Virol 73: 3994-4003. 117. Rutledge, EA, Halbert, CL, and Russell, DW (1998). Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 72: 309-319. 118. Muramatsu, S, Mizukami, H, Young, NS, and Brown, KE (1996). Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology 221: 208-217. 119. Chiorini, JA, Yang, L, Liu, Y, Safer, B, and Kotin, RM (1997). Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol 71: 6823-6833. 120. Chiorini, JA, Kim, F, Yang, L, and Kotin, RM (1999). Cloning and characterization of adeno-associated virus type 5. J Virol 73: 1309-1319. 121. Samulski, RJ, Srivastava, A, Berns, KI, and Muzyczka, N (1983). Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV. Cell 33: 135-143. 122. Gao, GP, Alvira, MR, Wang, L, Calcedo, R, Johnston, J, and Wilson, JM (2002). Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 99: 11854-11859. 123. Gao, G, Vandenberghe, LH, Alvira, MR, Lu, Y, Calcedo, R, Zhou, X, et al. (2004). Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol 78: 6381-6388. 124. Mori, S, Wang, L, Takeuchi, T, and Kanda, T (2004). Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology 330: 375-383. 125. Schmidt, M, Voutetakis, A, Afione, S, Zheng, C, Mandikian, D, and Chiorini, JA (2008). Adeno-associated virus type 12 (AAV12): a novel AAV serotype with sialic acid- and heparan sulfate proteoglycan-independent transduction activity. J Virol 82: 1399-1406. 126. Gao, G, Alvira, MR, Somanathan, S, Lu, Y, Vandenberghe, LH, Rux, JJ, et al. (2003). Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci U S A 100: 6081-6086. 127. Nonnenmacher, M, and Weber, T (2012). Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 19: 649-658. 128. Nakai, H, Fuess, S, Storm, TA, Muramatsu, S, Nara, Y, and Kay, MA (2005). Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J Virol 79: 214-224. 129. Inagaki, K, Fuess, S, Storm, TA, Gibson, GA, McTiernan, CF, Kay, MA, et al. (2006). Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 14: 45-53. 130. Glushakova, LG, Lisankie, MJ, Eruslanov, EB, Ojano-Dirain, C, Zolotukhin, I, Liu, C, et al. (2009). AAV3-mediated transfer and expression of the pyruvate dehydrogenase E1 alpha subunit gene causes metabolic remodeling and apoptosis of human liver cancer cells. Mol Genet Metab 98: 289-299. 131. Summerford, C, and Samulski, RJ (1998). Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 72: 1438-1445. 132. Qing, K, Mah, C, Hansen, J, Zhou, S, Dwarki, V, and Srivastava, A (1999). Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 5: 71-77. 133. Summerford, C, Bartlett, JS, and Samulski, RJ (1999). AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 5: 78-82. 134. Akache, B, Grimm, D, Pandey, K, Yant, SR, Xu, H, and Kay, MA (2006). The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J Virol 80: 9831-9836. 135. Kashiwakura, Y, Tamayose, K, Iwabuchi, K, Hirai, Y, Shimada, T, Matsumoto, K, et al. (2005). Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection. J Virol 79: 609-614. 136. Levy, HC, Bowman, VD, Govindasamy, L, McKenna, R, Nash, K, Warrington, K, et al. (2009). Heparin binding induces conformational changes in Adeno-associated virus serotype 2. J Struct Biol 165: 146-156. 137. Duan, D, Li, Q, Kao, AW, Yue, Y, Pessin, JE, and Engelhardt, JF (1999). Dynamin is required for recombinant adeno-associated virus type 2 infection. J Virol 73: 10371-10376. 138. Nam, HJ, Gurda, BL, McKenna, R, Potter, M, Byrne, B, Salganik, M, et al. (2011). Structural studies of adeno-associated virus serotype 8 capsid transitions associated with endosomal trafficking. J Virol 85: 11791-11799. 139. Kronenberg, S, Bottcher, B, von der Lieth, CW, Bleker, S, and Kleinschmidt, JA (2005). A conformational change in the adeno-associated virus type 2 capsid leads to the exposure of hidden VP1 N termini. J Virol 79: 5296-5303. 140. Girod, A, Wobus, CE, Zadori, Z, Ried, M, Leike, K, Tijssen, P, et al. (2002). The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. J Gen Virol 83: 973-978. 141. Stahnke, S, Lux, K, Uhrig, S, Kreppel, F, Hosel, M, Coutelle, O, et al. (2011). Intrinsic phospholipase A2 activity of adeno-associated virus is involved in endosomal escape of incoming particles. Virology 409: 77-83. 142. Johnson, JS, and Samulski, RJ (2009). Enhancement of adeno-associated virus infection by mobilizing capsids into and out of the nucleolus. J Virol 83: 2632-2644. 143. Im, DS, and Muzyczka, N (1990). The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity. Cell 61: 447-457. 144. Owens, RA, Weitzman, MD, Kyostio, SR, and Carter, BJ (1993). Identification of a DNA-binding domain in the amino terminus of adeno-associated virus Rep proteins. J Virol 67: 997-1005. 145. Weitzman, MD, Kyostio, SR, Kotin, RM, and Owens, RA (1994). Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc Natl Acad Sci U S A 91: 5808-5812. 146. Xiao, W, Berta, SC, Lu, MM, Moscioni, AD, Tazelaar, J, and Wilson, JM (1998). Adeno-associated virus as a vector for liver-directed gene therapy. J Virol 72: 10222-10226. 147. Nakai, H, Iwaki, Y, Kay, MA, and Couto, LB (1999). Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J Virol 73: 5438-5447. 148. McCarty, DM (2008). Self-complementary AAV vectors; advances and applications. Mol Ther 16: 1648-1656. 149. Perros, M, Spegelaere, P, Dupont, F, Vanacker, JM, and Rommelaere, J (1994). Cruciform structure of a DNA motif of parvovirus minute virus of mice (prototype strain) involved in the attenuation of gene expression. J Gen Virol 75 ( Pt 10): 2645-2653. 150. Riolobos, L, Reguera, J, Mateu, MG, and Almendral, JM (2006). Nuclear transport of trimeric assembly intermediates exerts a morphogenetic control on the icosahedral parvovirus capsid. J Mol Biol 357: 1026-1038. 151. Gray, SJ, Choi, VW, Asokan, A, Haberman, RA, McCown, TJ, and Samulski, RJ (2011). Production of recombinant adeno-associated viral vectors and use in in vitro and in vivo administration. Curr Protoc Neurosci Chapter 4: Unit 4 17. 152. Xiao, X, Li, J, and Samulski, RJ (1998). Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 72: 2224-2232. 153. Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ, Herzog, RW, Arruda, VR, et al. (2003). AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101: 2963-2972. 154. Koeberl, DD, Alexander, IE, Halbert, CL, Russell, DW, and Miller, AD (1997). Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors. Proc Natl Acad Sci U S A 94: 1426-1431. 155. Bartlett, JS, Samulski, RJ, and McCown, TJ (1998). Selective and rapid uptake of adeno-associated virus type 2 in brain. Hum Gene Ther 9: 1181-1186. 156. Nakai, H, Thomas, CE, Storm, TA, Fuess, S, Powell, S, Wright, JF, et al. (2002). A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J Virol 76: 11343-11349. 157. Grieger, JC, Choi, VW, and Samulski, RJ (2006). Production and characterization of adeno-associated viral vectors. Nat Protoc 1: 1412-1428. 158. Thomas, CE, Storm, TA, Huang, Z, and Kay, MA (2004). Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors. J Virol 78: 3110-3122. 159. White, SJ, Nicklin, SA, Buning, H, Brosnan, MJ, Leike, K, Papadakis, ED, et al. (2004). Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 109: 513-519. 160. Lisowski, L, Dane, AP, Chu, K, Zhang, Y, Cunningham, SC, Wilson, EM, et al. (2014). Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506: 382-386. 161. Wang, Z, Ma, HI, Li, J, Sun, L, Zhang, J, and Xiao, X (2003). Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther 10: 2105-2111. 162. McCarty, DM, Fu, H, Monahan, PE, Toulson, CE, Naik, P, and Samulski, RJ (2003). Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther 10: 2112-2118. 163. Ren, C, Kumar, S, Shaw, DR, and Ponnazhagan, S (2005). Genomic stability of self-complementary adeno-associated virus 2 during early stages of transduction in mouse muscle in vivo. Hum Gene Ther 16: 1047-1057. 164. Wang, JC, and Lynch, AS (1993). Transcription and DNA supercoiling. Curr Opin Genet Dev 3: 764-768. 165. Bertoni, R, Sette, A, Sidney, J, Guidotti, LG, Shapiro, M, Purcell, R, et al. (1998). Human class I super | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51710 | - |
| dc.description.abstract | 慢性B型肝炎病人體內帶有大量的病毒顆粒以及病毒蛋白。之前的研究認為這兩者是加速病人病情演化甚至造成肝癌的重要因素。現有的核苷(酸)類藥物雖然能夠有效的抑制病人體內的病毒量，但是卻無法減少病人血液中的病毒蛋白。除此之外，長期給予核苷(酸)類藥物藥治療容易使病人從體內已存在的病毒突變株中篩選出對藥物具有抗藥性的病毒株，這些都是目前臨床治療上所面臨的問題。不同於核苷(酸)類藥物，干擾RNA (RNA interference, RNAi) 除了可以很有效的抑制B型肝炎病人體內的病毒量，更可以有效的抑制病人體內的病毒蛋白。在我們之前的研究，我們以雙股腺相關病毒當作載體，表現一段有效的干擾RNA，叫做S1。當我們把病毒打到B型肝炎轉殖鼠後，發現S1可以抑制老鼠血液中的病毒量達到數千至一萬倍左右。但是，在RNAi治療過程中篩選出對藥物具有抗藥性的病毒株仍然是一個潛在的問題。目前面對這樣的問題，其中一個解決的方法就是應用複合型干擾RNA，減少突變型病毒在藥物的使用過程逃脫，進而取代野生型病毒，變成優勢病毒株。本論文研究目的就是要在人肝嵌合小鼠模式評估已存在的抗藥性的病毒株對於干擾RNA治療成效的影響。其次，我們要篩選出若干個具有臨床應用效益的干擾RNA，希望透過應用複合型干擾RNA，減少突變型病毒在藥物使用的過程中逃脫。為了要找到更多有效的干擾RNA，我們用了一個名為PICKY的程式去預測可能有效的shRNA，再進一步在高壓注射 (hydrodynamic co-injection) 小鼠模式以及B型肝炎轉殖鼠去篩選這些可能有效的shRNA。最後我們找到有六個像S1一樣有效的干擾RNA。為了觀察RNAi治療是如何影響野生型及突變型HBV病毒之間的消長，以及研究複合型shRNA治療是否能夠防止突變型的HBV病毒逃脫。我們以9:1的比例，把野生型HBV病毒混合對S1具有抗藥性的病毒株 (T472C HBV)，接著去感染人類肝細胞嵌合小鼠。當兩種病毒已經穩定感染人類肝細胞嵌合小鼠後，打入可以表現一個或兩個干擾RNA的腺相關病毒。從實驗結果中，我們發現抗藥性的病毒株存在時，不僅會減低S1的治療效果，而且還會使得血液中的突變型T472C病毒株取代野生型病毒，變成優勢病毒株。但是當我們施予複合型干擾RNA時，則會同時抑制兩個病毒株，進而防止篩選出抗藥性病毒株。最後，我們還發現雖然RNAi治療可以有效的抑制HBV病毒，但它在五周的治療期間並不影響cccDNA的量以及野生型及突變型HBV病毒之間cccDNA的比例。為了研究長期RNAi治療是否會影響野生型及突變型HBV病毒之間cccDNA的比例，我們以S1 shRNA治療小鼠，並將實驗觀察周期延長到20周，最後我們發現，經過20周S1 shRNA的治療，突變型T472C HBV的cccDNA的比例明顯的上升。本篇研究我們不僅篩選出了數個和S1一樣有效的干擾RNA。而且我們也成功的在近似於臨床病的人類肝細胞嵌合小鼠的身上證明單一個干擾RNA會造成抗藥性的病毒株的逃脫，若是使用複合型干擾RNA則可以有效的抑制突變型的病毒的逃脫。 | zh_TW |
| dc.description.abstract | High serum viral DNA and proteins in chronic hepatitis B virus (HBV) patients are known positively correlated with development of severe liver complications, including cirrhosis and hepatocellular carcinoma. Nucleoside and nucleotide analogs (NA) treatment, although effective in reducing serum HBV DNA, has only a limited effect on viral antigenemia. Treatment of NA drugs often lead to selection from the quasispecies pool of pre-existing drug-resistant HBV variants with higher fitness. RNAi-based therapy is a promising alternative therapy for chronic HBV because it can reduce both serum HBV DNA and proteins. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. Moreover, serum HBV proteins were also greatly reduced in S1-treated mice. However, selection of RNAi-resistant variants could be a potential problem in the treatment of chronic HBV patients. In this study, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy and propose the use of combinatorial shRNA therapy to prevent viral escape. To obtain more HBV-targeting shRNAs with high potency in vivo that would allow us to perform combinatorial RNAi therapy, we applied the “PICKY” software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Although combinatorial therapy greatly reduced serum HBV DNA, it had little effect on the intrahepatic levels of covalently closed circular DNA (cccDNA), the major templates for viral transcription. However, long-term RNAi treatment did alter the ratio of wild-type to T472C HBV in the cccDNA level. Together, our results suggest that mono-shRNA therapy in chronic HBV patients might select shRNA-resistant HBV variants which can be prevented by combinatorial RNAi therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:45:45Z (GMT). No. of bitstreams: 1 ntu-104-F97445116-1.pdf: 4666194 bytes, checksum: 9df622b11aebc9259d4e3e36aac89e5c (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | Table of content 1
中文摘要 5 Abstract 7 Introduction 9 1. Hepatitis B virus (HBV) 9 1.1 HBV introduction 9 1.2 HBV proteins 10 1.3 HBV Replication cycle 13 1.4 Clinical outcome of chronic Hepatitis B (CHB) infection 14 1.5 Current therapies for chronic HBV infection 15 2. RNA interference (RNAi) 18 2.1 Mechanism of RNA interference 18 2.2 therapeutic applications of RNAi 19 2.3 RNAi therapy in HBV infection 20 2.4 challenges of RNAi-based therapy 20 3. Adeno-associated virus (AAV) 23 3.1. AAV introduction 23 3.2. DNA replication 27 3.3. Recombinant AAV vector 28 3.4. Double-strand AAV vector 29 4. Animal model of human HBV infection 30 4.1 Chimpanzee 30 4.2 Tupaia 31 4.3 Mouse 32 5. Specific aim and experimental design 35 Materials and Methods 37 1. Site-direct mutagenesis 37 2. PICKY software 37 3. Cell culture 38 4. Plasmid construction and prepare ation 38 4.1 pSuper/shRNA plasmid construction 38 4.2 pAAVEMBL/shRNA plasmid construction 39 5. In vitro experiment 40 5.1 Co-transfection 40 5.2 HBsAg measurment (homemade ELISA) 40 6. Recombinant AAV production and purification 41 6.1 Cotransfection (Calcium phosphate precipitation methods) 41 6.2 Harvest AAV vectors from cells 42 6.3 AAV vector purification 43 6.4 Viral vector quantification 44 7. Animal experiment 45 7.1 Mice and general manipulation 45 7.2 Hydrodynamic injection 46 7.3 HBV transgenic mice 47 7.4 Human liver chimeric mice 47 8. Serum sample analysis 49 8.1 Serum HBV DNA analysis 49 8.2 Serum HBsAg, HBeAg and Human albumin analysis 50 8.3 Serum alanine aminotransferase analysis 50 9. Histological analysis 50 10. Immunostaining 50 11. Liver HBV DNA, RNA and cccDNA analysis 52 11.1 Southern blot analysis of HBV replicative DNA 52 11.2 Northern blot analysis of RNA 53 11.3 cccDNA quantification 54 12. Analysis of AAV genome and transgene expression 56 12.1 Southern blot analysis of AAV viral genome in mice liver 56 12.2 Small RNA expression in mice liver 57 13. RT-qPCR 58 13.1 Quantitative measurement of mouse cytokine cytokine-induced gene expression by polymerase chain reaction 58 13.2 Quantitative measurement of mouse miR-122 levels by polymerase chain reaction 59 14. Sequence analysis of the HBV genome. 60 15. PCR-RFLP 61 Results 62 1. A mutant T472C HBV resists to RNAi therapy with S1 62 2. Screening of highly potent HBV-targeting shRNAs predicted using the PICKY software 63 2.1 Validation of reported shRNA candidates 63 2.2 Screening of PICKY-predicted shRNAs by co-transfection of HBV- and shRNA-encoding plasmids 64 2.3 Therapeutic effects of AAV8/shRNAs in HBV transgenic mice 65 2.4 Long-term therapeutic effects of AAV8/shRNAs in HBV transgenic mice 67 2.5 Safety profiles of PICKY-selected potent shRNAs 68 3. Prevention of viral escape by combinatorial shRNA treatment 69 3.1 Prevention of viral escape by hydrodynamic co-injection of HBV- and shRNA-encoding plasmids. 69 3.2 Therapeutic effects of AAV8/shRNAs in HBV-infected human liver chimeric mice 70 3.3 Dynamics of serum HBV variants under the treatment of RNAi therapy 73 3.4 Effects of RNAi therapy on cccDNA 75 3.5 Long-term suppressive effects of combinatorial RNAi therapy 76 3.6 Three potent shRNAs in combination could achieve long-term suppressive effects without selecting RNAi resistant mutant 77 Discussion 79 1. Selection of shRNA targets that is potent in vivo 79 2. Safety of RNAi-based gene therapy 80 3. Stability of adeno-associated virus vectors in vivo 82 4. Concern of neutralization antibodies in clinical applications of AAV vectors 83 5. Combinatorial RNAi therapy prevent selection of RNAi resistant mutants 84 6. Effects of RNAi therapy on intrahepatic cccDNA 88 References 89 Figure 1. T472C HBV is partially resistant to S1 shRNA. 110 Figure 2. Discrepancy between shRNA potency in vitro and in vivo. 111 Figure 3. Screening of PICKY-predicted shRNAs by in vitro co-transfection 112 Figure 4. Screening of PICKY-predicted shRNAs in HBV transgenic mice. 114 Figure 6. Expression of small hairpin RNA in the liver. 116 Figure 7. Time-course of effects of AAV8/shRNA treatment in HBV transgenic mice. 117 Figure 8. Toxicity profiles of PICKY-selected shRNAs. 119 Figure 9. Combinatorial shRNA treatment prevents HBV mutant escape in the hydrodynamic injection model. 120 Figure 10. Wild-type and T472C HBV infection in hu-FRG mice. 121 Figure 11. Evaluation of the therapeutic efficacy of AAV8/shRNAs in HBV-infected hu-FRG mice 122 Figure 12. Serum human albumin levels in HBV-infected hu-FRG mice treated with various AAV8/shRNA vectors. 123 Figure 13. Effect of shRNA treatment on intrahepatic HBcAg in HBV-infected hu-FRG mice. 124 Figure 14. Effect of shRNA treatment on intrahepatic HBsAg in HBV-infected hu-FRG mice. 125 Figure 15. Reduced intrahepatic HBV DNA and RNA levels in HBV-infected hu-FRG mice treated with the indicated AAV8/shRNA vectors. 126 Figure 16. HBV variant analysis in AAV8/shRNA-treated hu-FRG mice. 127 Figure 17. A single nucleotide mutation in the siRNA target sequence resulted in loss of sensitivity to P28. 128 Figure 18. Long-term therapeutic effects of AAV8/S1 treatment in HBV-infected hu-FRG and analysis of intrahepatic cccDNA 130 Figure 19. Long-term inhibition effects of combinatorial RNAi therapy in mix HBV-infected hu-FRG 131 Figure 20. Three potent shRNAs in combination could long-term inhibit HBV replication. 133 Appendix 1-Sequence candidates selected by PICKY software 134 Appendix 2-oligonucleotide pairs for small RNA probe synthesis 135 Appendix 3-oligonucleotide pairs for RT-qPCR 136 | |
| dc.language.iso | en | |
| dc.subject | 人類肝細胞嵌合小鼠 | zh_TW |
| dc.subject | RNA干擾 | zh_TW |
| dc.subject | 慢性B型肝炎 | zh_TW |
| dc.subject | 抗藥性B型肝炎病毒 | zh_TW |
| dc.subject | 腺相關病毒載體 | zh_TW |
| dc.subject | human liver chimeric mice | en |
| dc.subject | RNA interference | en |
| dc.subject | chronic hepatitis B | en |
| dc.subject | drug-resistant hepatitis B virus | en |
| dc.subject | adeno-associated virus | en |
| dc.title | 應用人肝嵌合小鼠模式發展以腺相關病毒攜帶複合型干擾RNA治療慢性B型肝炎 | zh_TW |
| dc.title | Development of AAV-mediated combinatorial RNAi therapy for chronic hepatitis B infection in human liver chimeric mice model | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 楊宏志(Hung-Chih Yang),莊雅慧(Ya-Hui Chuang),詹世鵬(Shih-Peng Chan),顧家綺(Chia-Chi Ku) | |
| dc.subject.keyword | RNA干擾,慢性B型肝炎,抗藥性B型肝炎病毒,腺相關病毒載體,人類肝細胞嵌合小鼠, | zh_TW |
| dc.subject.keyword | RNA interference,chronic hepatitis B,drug-resistant hepatitis B virus,adeno-associated virus,human liver chimeric mice, | en |
| dc.relation.page | 136 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-11-30 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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