簡易檢索 / 詳目顯示

研究生: 蔡宗翰
Tsai, Tsung-Han
論文名稱: 尋找重要訊息路徑:於斑馬魚小腦創傷復原進程
Seeking for the crucial cerebellar wound healing-related pathways after traumatic brain injury in Danio rerio
指導教授: 陳博現
Chen, Bor-Sen
口試委員: 陳博現
Chen, Bor-Sen
林俊良
Lin, Chun-Liang
莊永仁
Chuang, Yung-Jen
吳謂勝
Wu, Wesson
林澤
Lin, Che
學位類別: 碩士
Master
系所名稱: 電機資訊學院 - 電機工程學系
Department of Electrical Engineering
論文出版年: 2012
畢業學年度: 100
語文別: 英文
論文頁數: 56
中文關鍵詞: 斑馬魚腦部創傷傷口復原
外文關鍵詞: Danio rerio, traumatic brain injury, wound healing
相關次數: 點閱:2下載:0
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 對於大部分的多細胞動物,保持中樞神經系統正常運作絕對是攸關生死的課題之一,萬一中樞神經系統受到了損傷,動物們最好有方法讓受損的部位再生回來。再生是一個極有趣的生物現象,但目前我們對它細胞層次以及分子層次的機制不太了解。相對於人類的中樞神經系統無法再生,斑馬魚在中樞神經系統上的再生能力是非常強的,它可以再生多種中樞神經系統的器官及組織,包括小腦在內,所以拿它來做為研究中樞神經系統修復的機制是再適合不過了。在本研究中,我們使用了三種方式來分析斑馬魚小腦創傷修復過程的微陣列晶片數據,分別是時間序列分析、訊息路徑富集分析、轉錄因子富集分析、動態蛋白質互動網路分析。透過這些分析,我們希望回答的問題是那些訊息路徑調控了小腦部位受損組織的復原進程。從分析結果中,我們的確看到了許多顯著的訊息路徑在創傷復原的過程裡以不同的動態模式活躍著。此外,我們也發現一些轉錄因子可能維繫著不同動態模式的訊息路徑間的關聯性。這些發現讓我們更為清楚腦部創傷復原的分子機制,使我們朝人類中樞神經系統再生療法的目標更邁進了一步。


    The central nervous system (CNS) is the most important system to most of multicellular animals. Once the CNS gets damaged, animals had better regenerate it back. Regeneration is one of the most interesting biological phenomena but its molecular and cellular mechanisms are still unclear. Danio rerio is a good model to investigate these mechanisms since it can regenerate many types of CNS tissues, including cerebellum, while we humans cannot. In this study, we applied several frequently-adopted methods such as time series analysis, pathway enrichment analysis, and promoter analysis to the temporal microarray profile of zebrafish after traumatic brain injury, as well as constructed a wound healing-related protein-protein interaction (PPI) network of zebrafish with the dynamic cellular model and system identification approaches. According to these analyses, many significant pathways and crucial transcription factors in wound healing process were identified. From these important results, we can gain more insights into the specific molecular mechanisms in CNS regeneration process and make human CNS regeneration more feasible in the future.

    Abstract.............................................. ii Content............................................... iii List of Figures....................................... v List of tables........................................ vi List of supplemental materials........................ vii Introduction.......................................... 1 1.1 Traumatic brain injury............................ 2 1.2 Phases in wound healing process................... 3 1.3 Zebrafish model of cerebellar wound healing....... 4 Materials and Methods................................. 6 2.1 Overview of the process........................... 6 2.2 Data selection and preprocessing.................. 6 2.3 Selection of protein pool for rough PPI networks.. 7 2.4 Time series analysis and pathway analysis......... 8 2.5 Promoter analysis................................. 9 2.6 Dynamic model of wound healing-related cellular PPI network............................................... 10 2.7 Parameter identification of rough PPI network via time series microarray data................................ 11 2.8 Determination of significant interaction pairs.... 13 Results............................................... 15 3.1 Main patterns in the gene expression profile...... 15 3.2 Significant pathways in two identified phases..... 16 3.2.1 Acute responses................................. 16 3.2.2 Responses that positively correlate to the zebrafish motor disability pattern.............................. 18 3.2.3 Responses that negatively correlate to the zebrafish motor disability pattern.............................. 21 3.3 Construction of dynamic PPI network............... 22 3.4 Potential transcription factors leading to cerebellar wound healing......................................... 24 Discussion............................................ 27 Conclusion............................................ 31 Bibliography.......................................... 32

    1. Tanaka, E.M. and P. Ferretti, Considering the evolution of regeneration in the central nervous system. Nature Reviews Neuroscience, 2009. 10(10): p. 713-723.
    2. Horner, P.J. and F.H. Gage, Regenerating the damaged central nervous system. NATURE-LONDON-, 2000: p. 963-970.
    3. Kishimoto, N., K. Shimizu, and K. Sawamoto, Neuronal regeneration in a zebrafish model of adult brain injury. Disease Models & Mechanisms, 2012. 5(2): p. 200.
    4. Antos, C.L. and M. Brand, Regeneration of organs and appendages in Zebrafish: A window into underlying control mechanisms. eLS, 2010.
    5. Endo, T., et al., Brain regeneration in anuran amphibians. Development, growth & differentiation, 2007. 49(2): p. 121-129.
    6. Faul, M., et al., Traumatic brain injury in the United States: Emergency department visits, hospitalizations and deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 2010.
    7. Kizil, C., et al., Adult neurogenesis and brain regeneration in zebrafish. Developmental neurobiology, 2012. 72(3): p. 429-461.
    8. Singer, A.J. and R. Clark, Cutaneous wound healing. N Engl J Med, 1999. 341(10): p. 738-746.
    9. Stadelmann, W.K., A.G. Digenis, and G.R. Tobin, Physiology and healing dynamics of chronic cutaneous wounds. The American Journal of Surgery, 1998. 176(2): p. 26S-38S.
    10. Poss, K.D., L.G. Wilson, and M.T. Keating, Heart regeneration in zebrafish. Science, 2002. 298(5601): p. 2188-2190.
    11. Guo, Y., et al., Transcription factor Sox11b is involved in spinal cord regeneration in adult zebrafish. Neuroscience, 2011. 172: p. 329-341.
    12. Qin, Z., L.K. Barthel, and P.A. Raymond, Genetic evidence for shared mechanisms of epimorphic regeneration in zebrafish. Proceedings of the National Academy of Sciences, 2009. 106(23): p. 9310.
    13. Craig, S.E.L., A.A. Calinescu, and P.F. Hitchcock, Identification of the molecular signatures integral to regenerating photoreceptors in the retina of the zebra fish. Journal of ocular biology, diseases, and informatics, 2008. 1(2): p. 73-84.
    14. McCurley, A.T. and G.V. Callard, Time course analysis of gene expression patterns in zebrafish eye during optic nerve regeneration. Journal of experimental neuroscience, 2010. 2010(4): p. 17.
    15. Cameron, D.A., et al., Gene expression profiles of intact and regenerating zebrafish retina. Mol Vis, 2005. 11: p. 775-791.
    16. Postlethwait, J., et al., The zebrafish genome. Methods Cell Biol, 1999. 60: p. 149-63.
    17. Wang, Y.C. and B.S. Chen, Integrated cellular network of transcription regulations and protein-protein interactions. BMC Syst Biol, 2010. 4: p. 20.
    18. Joshi-Tope, G., et al., Reactome: a knowledgebase of biological pathways. Nucleic acids research, 2005. 33(suppl 1): p. D428-D432.
    19. Ernst, J. and Z. Bar-Joseph, STEM: a tool for the analysis of short time series gene expression data. BMC bioinformatics, 2006. 7(1): p. 191.
    20. Thomas, P.D., et al., PANTHER: a library of protein families and subfamilies indexed by function. Genome research, 2003. 13(9): p. 2129-2141.
    21. Cho, R.J. and M.J. Campbell, Transcription, genomes, function. Trends in Genetics, 2000. 16(9): p. 409-415.
    22. Sui, S.J.H., et al., oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes. Nucleic acids research, 2005. 33(10): p. 3154-3164.
    23. Alon, U., An introduction to systems biology : design principles of biological circuits. Chapman & Hall/CRC mathematical and computational biology series2007, Boca Raton, FL: Chapman & Hall/CRC. xvi, 301 p., 4 p. of plates.
    24. Coleman, T.F. and L.A. Hulbert, A Direct Active Set Algorithm for Large Sparse Quadratic Programs with Simple Bounds. Mathematical Programming, 1989. 45(3): p. 373-406.
    25. Bar-Joseph, Z., et al., A new approach to analyzing gene expression time series data, in Proceedings of the sixth annual international conference on Computational biology2002, ACM: Washington, DC, USA. p. 39-48.
    26. De Boor, C., A practical guide to splines : with 32 figures. Rev. ed. Applied mathematical sciences2001, New York: Springer. xviii, 346 p.
    27. Orntoft, T.F., et al., Genome-wide study of gene copy numbers, transcripts, and protein levels in pairs of non-invasive and invasive human transitional cell carcinomas. Molecular & Cellular Proteomics, 2002. 1(1): p. 37-45.
    28. Newman, J.R.S., et al., Single-cell proteomic analysis of S-cerevisiae reveals the architecture of biological noise. Nature, 2006. 441(7095): p. 840-846.
    29. Akaike, H., New Look at Statistical-Model Identification. Ieee Transactions on Automatic Control, 1974. Ac19(6): p. 716-723.
    30. Johansson, R., System modeling and identification. Prentice Hall information and system sciences series1993, Englewood Cliffs, NJ: Prentice Hall. xiii, 512 p.
    31. Lu, X. and P. Richardson, Inflammation near the nerve cell body enhances axonal regeneration. The Journal of neuroscience, 1991. 11(4): p. 972-978.
    32. Rajaram, M.V.S., et al., Akt/Protein kinase B modulates macrophage inflammatory response to Francisella infection and confers a survival advantage in mice. The Journal of Immunology, 2006. 177(9): p. 6317-6324.
    33. Collins, W., A review and update of experiment and clinical studies of spinal cord injury. Spinal Cord, 1983. 21(4): p. 204-219.
    34. Yoles, E., et al., GM1 reduces injury-induced metabolic deficits and degeneration in the rat optic nerve. Investigative ophthalmology & visual science, 1992. 33(13): p. 3586-3591.
    35. Lotan, M. and M. Schwartz, Cross talk between the immune system and the nervous system in response to injury: implications for regeneration. The FASEB journal, 1994. 8(13): p. 1026-1033.
    36. Orrenius, S., B. Zhivotovsky, and P. Nicotera, Regulation of cell death: the calcium-apoptosis link. Nature Reviews Molecular Cell Biology, 2003. 4(7): p. 552-565.
    37. Buttke, T.M. and P.A. Sandstrom, Oxidative stress as a mediator of apoptosis. Immunology today, 1994. 15(1): p. 7.
    38. Hall, E.D. and J.M. Braughler, Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free radical biology & medicine, 1989. 6(3): p. 303.
    39. Tyurin, V.A., et al., Oxidative stress following traumatic brain injury in rats. Journal of neurochemistry, 2000. 75(5): p. 2178-2189.
    40. Cross, M.J. and L. Claesson-Welsh, FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends in pharmacological sciences, 2001. 22(4): p. 201-207.
    41. Köster, R.W. and S.E. Fraser, FGF signaling mediates regeneration of the differentiating cerebellum through repatterning of the anterior hindbrain and reinitiation of neuronal migration. The Journal of neuroscience, 2006. 26(27): p. 7293-7304.
    42. Ridley, A.J., Rho GTPases and cell migration. Journal of Cell Science, 2001. 114(15): p. 2713-2722.
    43. Giancotti, F.G. and E. Ruoslahti, Integrin signaling. Science, 1999. 285(5430): p. 1028-1033.
    44. Lin, M.T. and M.F. Beal, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 2006. 443(7113): p. 787-795.
    45. Lukacs, N.W., Role of chemokines in the pathogenesis of asthma. Nature Reviews Immunology, 2001. 1(2): p. 108-116.
    46. Vicente-Manzanares, M., et al., The leukocyte cytoskeleton in cell migration and immune interactions. International review of cytology, 2002. 216: p. 233-289.
    47. Gumbiner, B.M., Regulation of cadherin adhesive activity. The Journal of cell biology, 2000. 148(3): p. 399-404.
    48. Neves, S.R., P.T. Ram, and R. Iyengar, G protein pathways. Science's STKE, 2002. 296(5573): p. 1636.
    49. Alkjaersig, N., A.P. Fletcher, and S. Sherry, The mechanism of clot dissolution by plasmin. Journal of Clinical Investigation, 1959. 38(7): p. 1086.
    50. Dyer, S.A. and J.S. Dyer, Cubic-spline interpolation: Part 1. Ieee Instrumentation & Measurement Magazine, 2001. 4(1): p. 44-46.
    51. Smith, L.L., Acute inflammation: the underlying mechanism in delayed onset muscle soreness? Medicine and science in sports and exercise, 1991. 23(5): p. 542.
    52. Yu, F., et al., Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene, 2011. 30(18): p. 2161-2172.
    53. Moore, D.L., et al., KLF family members regulate intrinsic axon regeneration ability. Science, 2009. 326(5950): p. 298-301.
    54. Gilmore, T.D., Introduction to NF-κB: players, pathways, perspectives. Oncogene, 2006. 25(51): p. 6680-6684.
    55. Sharrocks, A.D., The ETS-domain transcription factor family. Nature Reviews Molecular Cell Biology, 2001. 2(11): p. 827-837.
    56. Chen, X., et al., Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. Journal of Biological Chemistry, 2001. 276(32): p. 30423-30428.
    57. Yoon, H.S., X. Chen, and V.W. Yang, Krüppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. Journal of Biological Chemistry, 2003. 278(4): p. 2101-2105.
    58. Andrianantoandro, E., et al., Synthetic biology: new engineering rules for an emerging discipline. Molecular systems biology, 2006. 2(1).

    無法下載圖示 全文公開日期 本全文未授權公開 (校內網路)
    全文公開日期 本全文未授權公開 (校外網路)
    全文公開日期 本全文未授權公開 (國家圖書館:臺灣博碩士論文系統)
    QR CODE