以斑馬魚作為研究心臟修復及藥物對心律影響的模型

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研究生：	黃威彰 Huang, Wei-Chang
論文名稱：	以斑馬魚作為研究心臟修復及藥物對心律影響的模型 Zebrafish: a predictive model for assessing cardiac repair and pharmacological effects on cardiac rhythm
指導教授：	莊永仁
口試委員:	蘇士哲張壯榮溫志宏陳廷碩
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	123
中文關鍵詞：	斑馬魚、心肌梗塞、心臟再生、發炎反應、心律不整、麻醉、心電圖
外文關鍵詞：	Zebrafish, Myocardial infarction, Heart regeneration, Inflammation, Cardiac arrhythmias, Anesthesia, Electrocardiography
相關次數：	點閱：2 下載：0
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心血管疾病對人類的健康造成極大威脅，在已開發國家造成的死亡人數比率相當高，其致死率甚至超過癌症。其中，心肌梗塞是常見的心血管疾病，病患因缺血及缺氧造成了梗塞血管下游心臟肌肉細胞的壞死，最終會導致心衰竭及死亡；至目前為止，臨床上仍難有積極的方法去促進受損心肌的修復再生。而另一種致命的心血管疾病，心律不整，則肇因心臟的異常電生理活動，與心肌梗塞亦具關聯性，發作時相當危險，常會導致心臟驟停和病人猝死。因而開發治療心血管疾病的藥物及方法，是刻不容緩的事。
斑馬魚為一近年來興起的模式生物，常被用來模擬人類疾病發生過程。斑馬魚擁有許多的優點，包括: 便宜並且易飼養；胚胎透明且在母體外發育，利於觀察；斑馬魚的基因組已被解碼定序完成。更重要的是，斑馬魚保留有和人類似的心血管循環系統，斑馬魚因而常被運用在心血管研究。在我們的研究中，利用斑馬魚研究系統獨特的優勢，我們開發出兩個重要的心血管功能評估平台：一為斑馬魚心臟修復模組，另一是斑馬魚心電圖監控模組。在第一部分的心臟修復模組，我們研究固醇類消炎藥物對傷口修復的影響，我們發現抑制發炎反應會妨礙斑馬魚的心臟修復，顯著地抑制血管新生和細胞複製。在第二部分的心電圖模組，我們則開發了即時活體斑馬魚心電圖技術，並且利用此技術測試我們開發出的新型麻醉配方，我們發現新配方能有效減少麻醉劑對生物造成的嚴重副作用:心跳速度降低及心律不整。新配方因而能有效地延長麻醉時間及降低實驗動物死亡率。
綜而言之，我們用斑馬魚建立了一個新穎且獨特的心血管分析平台，未來能用它來快速篩選出潛在的促進或是抑制心臟修復的藥物; 而獨特的斑馬魚心電圖技術則能夠協助篩選出潛在可能引起心律失常的危險藥物。把兩者結合，這樣的整合式平台除了能用於心血管疾病研究和臨床前藥物的篩選，未來並且有淺力成為商業化的專業委託實驗平台。

Cardiovascular diseases have been the leading cause of death worldwide for a long time. Ischemic heart disease such as myocardial infarction is a common type of cardiovascular diseases. During myocardial infarction, blood supply to the heart is decreased due to occlusion of coronary arteries. The subsequent shortage of nutrients and oxygen lead to cardiomyocytes death in the infarction region. If a patient survives from a myocardial infarction episode, the resulting scar tissues in the heart muscles may interfere the synchronized beating of the heart and will cause heart failure. On the other hand, cardiac arrhythmia is another life-threatening condition which may occur after heart attack or result from abnormal electrical activities in the heart. Similar to myocardial infarction, cardiac arrhythmia may lead to acute heart arrest and sudden death. There are increased efforts on research aiming to either prevent or treat this class of diseases.
As an emerging model organism for human diseases, several features of zebrafish (Danio rerio), such as its rapid and external development, easily tractable genetics, conserved cardiovascular system, and transparency, make it ideal for cardiovascular research. Giving these unique advantages over other animal models, we used zebrafish to establish two major assessment platforms for biomedical research: one is cardiac repair model and the other is zebrafish electrocardiography model.
In the first part of this thesis work, we found that applying the steroid anti-inflammatory drug during injury would hinder the cardiac repair capacity of zebrafish. The disrupted wound healing process accompanied with decreased angiogenesis and cell proliferation. In the second part of our work, we developed a new combinative formula of anesthetics for long-term anesthesia of zebrafish. This novel approach has minimized adverse effects in cardiac function, and its advantages are demonstrated by cardiac rhythm analysis using both the adult zebrafish and isolated heart electrocardiogram systems.
In conclusion, we established a zebrafish-based assessment module for cardiovascular diseases that could enhance cardiac repair research in the future. The unique zebrafish electrocardiogram system may also enable cardiotoxicity profiling. Integration of the zebrafish cardiac repair model and ECG system serves not only as a comprehensive platform for cardiovascular research, but also as commercial CRO tools for pre-clinical drug screening.

TABLE OF CONTENTS
中文摘要    1
ABSTRACT    2
ABBREVIATIONS    3
CHAPTER 1  GENERAL INTRODUCTION    5
1.1 Zebrafish, a popular model organism for biomedical research    5
1.2 Cardiovascular diseases & cardiac repair assessment in zebrafish    9
1.3 Cardiac arrhythmias & Electrocardiogram assessment in zebrafish    12
CHAPTER 2  MATERIALS AND METHODS    15
2.1 Cardiac repair assessment in zebrafish    15
2.1.1 Zebraﬁsh husbandry & Ethics statement    15
2.1.2 Ventricular resection & drug delivery for suppressing immune system    15
2.1.3 RNA isolation and RT-qPCR (real-time quantitative PCR)    16
2.1.4 Microarray and data analysis    17
2.1.5 Histology    19
2.1.6 BrdU injection    20
2.1.7 Immunofluorescence staining    20
2.1.8 Statistic    21
2.1.9 Primary epicardium cell explants assay and Immunocytochemistry    22
2.2 Cardiac rhythm assessment in zebrafish    23
2.2.1 Anesthetic preparation    23
2.2.2 Anesthesia profiles of the adult zebrafish    23
2.2.3 Electrocardiography (ECG) of adult zebrafish    24
2.2.4 Electrocardiography of isolated hearts    25
2.2.5 Anesthesia test of the embryonic zebrafish    25
2.2.6 Application- caudal fin amputation and observation    26
CHAPTER 3  CARDIAC REPAIR ASSESSMENT IN ZEBRAFISH: Glucocorticoid disrupted immune responses and hindered cardiac repair in adult zebrafish    27
3.1 Background and Specific Aims    27
3.2 Results    30
3.2.1 Heart regeneration in zebrafish    30
3.2.2 Important stages during cardiac repair of zebrafish    30
3.2.3 Large elevation of pro-inflammatory cytokines at the early stage of cardiac repair in adult zebrafish    31
3.2.4 Inflammation was required to complete cardiac repair in adult zebrafish    34
3.2.5 Global gene expression analysis identified significant genes down-regulated by beclomethasone in impaired healing hearts    37
3.2.6 Beclomethasone reduced the expression of key pro-inflammatory genes and phagocyte recruitment after cardiac injury    38
3.2.7 Angiogenesis was impaired in glucocorticoid-treated zebrafish    40
3.2.8 Cell proliferation was also impeded in glucocorticoid-treated zebrafish    42
3.2.9 Wnt16 was inhibited by beclomethasone and may be required for cardiac repair    44
3.3 Discussion & Conclusion    46
3.4 Prospects: Epithelial-Mesenchymal-Transition in epicardium during cardiac repair    51
CHAPTER 4 CARDIAC RHYTHM ASSESSMENT IN ZEBRAFISH:  The anesthetic mixture of MS-222 and isoflurane prolongs anesthesia time and hads minimizes cardiac rhythm side effects in adult zebrafish    53
4.1 Background and Specific Aims    53
4.2 Results    56
4.2.1 Developing the electrocardiography (ECG) technique for adult zebrafish and isolated hearts of zebrafish    56
4.2.2 Combined use of MS-222 and isoflurane prolongs stage 4 anesthesia time in adult zebrafish    58
4.2.3 Equal dosages of MS-222 and isoflurane anesthetized fish efficiently    61
4.2.4 Guidance for applying the combined formula    62
4.2.5 Combined formula had a minimal effect on zebrafish heart rates    63
4.2.6 Combined formula of MS-222 and isoflurane can also be used on embryonic zebrafish    65
4.2.7 Application of the combined anesthetic formula of MS-222 and isoflurane    65
4.3 Discussion & Conclusion    67
CHAPTER 5  SUMMARY    69
CHAPTER 6  PERSPECTIVE    71
APPENDIX: TRANSPARENT ADULT ZEBRAFISH, CITRINE, FACILITATES BIOMEDICAL RESEARCH    74
REFERENCES    80
TABLES    89
Table.1 Primer list for RT-qPCR    89
Table.2 Gene ontology analysis of differential expressed genes    90
Table.3 Induction time required to reach stage 4 anesthesia    91
Table.4 Heart rates (beats/minute) under anesthesia in embryonic zebrafish    92
FIGURES    93
Fig.1 Zebrafish regenerate damaged heart within 1 month.    93
Fig.2 Time scale and important stages during wound healing.    94
Fig.3 Elevation of pro-inflammatory genes expression during cardiac repair.    95
Fig.4 Treatment of glucocorticoid inhibits zebrafish fin regeneration.    96
Fig.5 Treatment of glucocorticoid after injury impaired cardiac repair in zebrafish.    97
Fig.6 Treatment with ibuprofen also caused impaired cardiac repair in zebrafish.    98
Fig.7 Beclomethasone and ibuprofen treatment repress the immune responses efficiently.    99
Fig.8 Microarray analysis identified healing responsive D. rerio probes down-regulated in the impaired healing heart.    100
Fig.9 Glucocorticoid treatment reduced pro-inflammatory gene expression and phagocytes recruitment after cardiac injury.    101
Fig.10 Angiogenesis was hindered in the glucocorticoid-treated zebrafish during process of cardiac repair.    102
Fig.11 Cell proliferation was hindered in the glucocorticoid-treated zebrafish during cardiac repair.    104
Fig.12 Wnt16 was inhibited by beclomethasone at early cardiac repair    106
Fig.13 Primary epicardium cells explants system.    107
Fig.14 PGE2 induced epithelial-mesenchymal-transition like morphological changes in primary epicardium cells.    108
Fig.15 The adult zebrafish electrocardiography system.    109
Fig.16 The isolated heart electrocardiography platform in zebrafish.    110
Fig.17 Time for reaching stage 5 anesthesia and for recovery.    111
Fig.18 Anesthesia with isoflurane.    112
Fig.19 Anesthesia with different combination of MS-222 and isoflurane.    113
Fig.20 ECG assessment on the effects of different preparation of anesthetics.    114
Fig.21 Isolated heart ECG assessment on the effects of different preparations of anesthetics.    115
Fig.22 Fin amputation and real-time observation of phagocytes recruitment.    116
APPENDIX FIGURES    117
Appendix Fig.1 Chemical structure of the compounds used to treat zebrafish.    117
Appendix Fig.2 Citrine- a novel transparent zebrafish line created in National Tsing-Hua University, Taiwan.    118
Appendix Fig.3 Preparation of transparent zebrafish.    119
Appendix Fig.4 Citrine served as a tool for real time observation of inner organs.    120
Appendix Fig.5 Heart specific transgenic fluorescent zebrafish.    121
Appendix Fig.6 Vasculature specific transgenic fluorescent zebrafish.    122
APPENDIX- PUBLISHED ARTICLES RELATED TO THE THESIS    123
                                

REFERENCES
Abramoff MD, Magelhaes PJ, Ram SJ. 2004. Image Processing with ImageJ. Biophotonics International 11(7):36-42.
Alfaro CL. 2001. Emerging role of drug interaction studies in drug development: the good, the bad, and the unknown. Psychopharmacol Bull 35(4):80-93.
Amrein R, Hetzel W, Allen SR. 1995. Co-induction of anaesthesia: the rationale. Eur J Anaesthesiol Suppl 12:5-11.
Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DY, Tristani-Firouzi M, Chi NC. 2007. Zebrafish model for human long QT syndrome. Proc Natl Acad Sci U S A 104(27):11316-21.
Arnoux V, Côme C, Kusewitt D, Hudson L, Savagner P. 2005. Cutaneous Wound Reepithelialization. Rise and Fall of Epithelial Phenotype. Springer US. p. 111-134.
Ballesteros KA, Sikorski A, Orfila JE, Martinez JL, Jr. 2012. Effects of inhaled anesthetic isoflurane on long-term potentiation of CA3 pyramidal cell afferents in vivo. Int J Gen Med 5:935-42.
Barros-Becker F, Romero J, Pulgar A, Feijoo CG. 2012. Persistent oxytetracycline exposure induces an inflammatory process that improves regenerative capacity in zebrafish larvae. PLoS One 7(5):e36827.
Barros TP, Alderton WK, Reynolds HM, Roach AG, Berghmans S. 2008. Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Br J Pharmacol 154(7):1400-13.
Barut BA, Zon LI. 2000. Realizing the potential of zebrafish as a model for human disease. Physiol Genomics 2(2):49-51.
Becker T, Lieberoth BC, Becker CG, Schachner M. 2005. Differences in the regenerative response of neuronal cell populations and indications for plasticity in intraspinal neurons after spinal cord transection in adult zebrafish. Mol Cell Neurosci 30(2):265-78.
Beis D, Bartman T, Jin SW, Scott IC, D'Amico LA, Ober EA, Verkade H, Frantsve J, Field HA, Wehman A et al. . 2005. Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development. Development 132(18):4193-204.
Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H et al. . 2009. Evidence for cardiomyocyte renewal in humans. Science 324(5923):98-102.
Bernhardt RR, Tongiorgi E, Anzini P, Schachner M. 1996. Increased expression of specific recognition molecules by retinal ganglion cells and by optic pathway glia accompanies the successful regeneration of retinal axons in adult zebrafish. J Comp Neurol 376(2):253-64.
Bui AL, Horwich TB, Fonarow GC. 2011. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 8(1):30-41.
Cakir Y, Strauch SM. 2005. Tricaine (MS-222) is a safe anesthetic compound compared to benzocaine and pentobarbital to induce anesthesia in leopard frogs (Rana pipiens). Pharmacol Rep 57(4):467-74.
Chen FF, Lin WH, Lin SC, Kuo JH, Chu HY, Huang WC, Chuang YJ, Lee SC, Sue SC. 2012. Significance of heparin binding to basic residues in homologous to the amino terminus of hepatoma-derived growth factor and related proteins. Glycobiology 22(5):649-61.
Chen IH, Wang HH, Hsieh YS, Huang WC, Yeh HI, Chuang YJ. 2013. PRSS23 is essential for the Snail-dependent endothelial-to-mesenchymal transition during valvulogenesis in zebrafish. Cardiovasc Res 97(3):443-53.
Chen JN, Fishman MC. 1996. Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation. Development 122(12):3809-16.
Chico TJ, Ingham PW, Crossman DC. 2008. Modeling cardiovascular disease in the zebrafish. Trends Cardiovasc Med 18(4):150-5.
Choi WY, Poss KD. 2012. Cardiac regeneration. Curr Top Dev Biol 100:319-44.
Clements WK, Kim AD, Ong KG, Moore JC, Lawson ND, Traver D. 2011. A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. Nature 474(7350):220-4.
Connolly DT. 1991. Vascular permeability factor: a unique regulator of blood vessel function. J Cell Biochem 47(3):219-23.
Craig MP, Gilday SD, Hove JR. 2006. Dose-dependent effects of chemical immobilization on the heart rate of embryonic zebrafish. Lab Anim (NY) 35(9):41-7.
Davis JM, Ramakrishnan L. 2009. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136(1):37-49.
Dooley K, Zon LI. 2000. Zebrafish: a model system for the study of human disease. Curr Opin Genet Dev 10(3):252-6.
Eger EI, 2nd, Raines DE, Shafer SL, Hemmings HC, Jr., Sonner JM. 2008. Is a new paradigm needed to explain how inhaled anesthetics produce immobility? Anesth Analg 107(3):832-48.
Eimon PM, Rubinstein AL. 2009. The use of in vivo zebrafish assays in drug toxicity screening. Expert Opin Drug Metab Toxicol 5(4):393-401.
Frangogiannis NG. 2012. Regulation of the inflammatory response in cardiac repair. Circ Res 110(1):159-73.
Frazier DT, Narahashi T. 1975. Tricaine (MS-222): effects on ionic conductances of squid axon membranes. Eur J Pharmacol 33(2):313-7.
Gaziano TA. 2007. Reducing The Growing Burden Of Cardiovascular Disease In The Developing World. Health Affairs 26(1):13-24.
Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, Weidinger G, Puder M, Daley GQ, Moon RT et al. . 2009. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 136(6):1136-47.
Grush J, Noakes DL, Moccia RD. 2004. The efficacy of clove oil as an anesthetic for the zebrafish, Danio rerio (Hamilton). Zebrafish 1(1):46-53.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. 2008. Wound repair and regeneration. Nature 453(7193):314-21.
Hall C, Flores MV, Storm T, Crosier K, Crosier P. 2007. The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish. BMC Dev Biol 7:42.
Hassel D, Scholz EP, Trano N, Friedrich O, Just S, Meder B, Weiss DL, Zitron E, Marquart S, Vogel B et al. . 2008. Deficient zebrafish ether-a-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants. Circulation 117(7):866-75.
Hecker L, Khait L, Sessions SK, Birla RK. 2008. Functional evaluation of isolated zebrafish hearts. Zebrafish 5(4):319-22.
Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. 2007. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13(8):970-4.
Hsu CH, Wen ZH, Lin CS, Chakraborty C. 2007. The zebrafish model: use in studying cellular mechanisms for a spectrum of clinical disease entities. Curr Neurovasc Res 4(2):111-20.
Huang WC, Hsieh YS, Chen IH, Wang CH, Chang HW, Yang CC, Ku TH, Yeh SR, Chuang YJ. 2010. Combined use of MS-222 (tricaine) and isoflurane extends anesthesia time and minimizes cardiac rhythm side effects in adult zebrafish. Zebrafish 7(3):297-304.
Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S. 1996. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 8(7):548-56.
Isogai S, Horiguchi M, Weinstein BM. 2001. The vascular anatomy of the developing zebrafish: an atlas of embryonic and early larval development. Dev Biol 230(2):278-301.
Jagadeeswaran P, Cykowski M, Thattaliyath B. 2004. Vascular occlusion and thrombosis in zebrafish. Methods Cell Biol 76:489-500.
Jiang B, Liao R. 2010. The paradoxical role of inflammation in cardiac repair and regeneration. J Cardiovasc Transl Res 3(4):410-6.
Jin SW, Beis D, Mitchell T, Chen JN, Stainier DY. 2005. Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development 132(23):5199-209.
Jolly DW, Mawdesley-Thomas LE, Bucke D. 1972. Anaesthesia of fish. Vet Rec 91(18):424-6.
Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC. 2010. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464(7288):606-9.
Kalluri R. 2009. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119(6):1417-9.
Kari G, Rodeck U, Dicker AP. 2007. Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharmacol Ther 82(1):70-80.
Keene JL, Noakes DLG, Moccia RD, Soto CG. 1998. The efficacy of clove oil as an anaesthetic for rainbow trout, <i>Oncorhynchus mykiss</i> (Walbaum). Aquaculture Research 29(2):89-101.
Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DY, Poss KD. 2010. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464(7288):601-5.
Kim J, Wu Q, Zhang Y, Wiens KM, Huang Y, Rubin N, Shimada H, Handin RI, Chao MY, Tuan TL et al. . 2010. PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts. Proc Natl Acad Sci U S A 107(40):17206-10.
Klebanoff SJ. 2005. Myeloperoxidase: friend and foe. J Leukoc Biol 77(5):598-625.
Kleber AG, Rudy Y. 2004. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 84(2):431-88.
Knighton DR, Phillips GD, Fiegel VD. 1990. Wound healing angiogenesis: indirect stimulation by basic fibroblast growth factor. J Trauma 30(12 Suppl):S134-44.
Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM. 1992. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089):1798-801.
Kopp R, Schwerte T, Pelster B. 2005. Cardiac performance in the zebrafish breakdance mutant. J Exp Biol 208(Pt 11):2123-34.
Koster RW, Fraser SE. 2006. FGF signaling mediates regeneration of the differentiating cerebellum through repatterning of the anterior hindbrain and reinitiation of neuronal migration. J Neurosci 26(27):7293-304.
Kuraitis D, Ruel M, Suuronen EJ. 2011. Mesenchymal stem cells for cardiovascular regeneration. Cardiovasc Drugs Ther 25(4):349-62.
Laflamme MA, Murry CE. 2011. Heart regeneration. Nature 473(7347):326-35.
Lafontant PJ, Burns AR, Grivas JA, Lesch MA, Lala TD, Reuter SP, Field LJ, Frounfelter TD. 2012. The giant danio (D. aequipinnatus) as a model of cardiac remodeling and regeneration. Anat Rec (Hoboken) 295(2):234-48.
Lawson ND, Weinstein BM. 2002. In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248(2):307-18.
Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD. 2006. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127(3):607-19.
Lien CL, Schebesta M, Makino S, Weber GJ, Keating MT. 2006. Gene expression analysis of zebrafish heart regeneration. PLoS Biol 4(8):e260.
Lieschke GJ, Currie PD. 2007. Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8(5):353-67.
Lin YL, Kung MF. 2009. Magnitude of QT prolongation associated with a higher risk of Torsades de Pointes. Pharmacoepidemiol Drug Saf 18(3):235-9.
Livak KJ, Schmittgen TD. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402-8.
Logan CY, Nusse R. 2004. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781-810.
Luo H, Chen Z, Jin H, Zhuang M, Wang T, Su C, Lei Y, Zou J, Zhong B. Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer. J Exp Clin Cancer Res 30:6.
Manuel Gonzalez-Rosa J, Peralta M, Mercader N. 2012. Pan-epicardial lineage tracing reveals that epicardium derived cells give rise to myofibroblasts and perivascular cells during zebrafish heart regeneration. Dev Biol.
Martin P. 1997. Wound healing--aiming for perfect skin regeneration. Science 276(5309):75-81.
Mathew LK, Sengupta S, Kawakami A, Andreasen EA, Lohr CV, Loynes CA, Renshaw SA, Peterson RT, Tanguay RL. 2007. Unraveling tissue regeneration pathways using chemical genetics. J Biol Chem 282(48):35202-10.
Mathews MB, Bernstein RM, Franza BR, Jr., Garrels JI. 1984. Identity of the proliferating cell nuclear antigen and cyclin. Nature 309(5966):374-6.
Matthews M, Varga ZM. 2012. Anesthesia and euthanasia in zebrafish. ILAR J 53(2):192-204.
McGrath P, Li CQ. 2008. Zebrafish: a predictive model for assessing drug-induced toxicity. Drug Discov Today 13(9-10):394-401.
Mescher AL, Neff AW. 2005. Regenerative capacity and the developing immune system. Adv Biochem Eng Biotechnol 93:39-66.
Milan DJ, Jones IL, Ellinor PT, MacRae CA. 2006. In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation. Am J Physiol Heart Circ Physiol 291(1):H269-73.
Mizgireuv IV, Revskoy SY. 2006. Transplantable tumor lines generated in clonal zebrafish. Cancer Res 66(6):3120-5.
Moss JB, Koustubhan P, Greenman M, Parsons MJ, Walter I, Moss LG. 2009. Regeneration of the pancreas in adult zebrafish. Diabetes 58(8):1844-51.
Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S. 2004. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 287(6):H2670-6.
Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. 2008. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis 29(11):2227-35.
Nemtsas P, Wettwer E, Christ T, Weidinger G, Ravens U. 2009. Adult zebrafish heart as a model for human heart? An electrophysiological study. J Mol Cell Cardiol.
Nesan D, Vijayan MM. 2012. Embryo exposure to elevated cortisol level leads to cardiac performance dysfunction in zebrafish. Mol Cell Endocrinol.
Nicoli S, Ribatti D, Cotelli F, Presta M. 2007. Mammalian tumor xenografts induce neovascularization in zebrafish embryos. Cancer Res 67(7):2927-31.
North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ, Bowman TV, Jang IH, Grosser T et al. . 2007. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447(7147):1007-11.
North TE, Zon LI. 2003. Modeling human hematopoietic and cardiovascular diseases in zebrafish. Dev Dyn 228(3):568-83.
Patton EE, Zon LI. 2005. Taking human cancer genes to the fish: a transgenic model of melanoma in zebrafish. Zebrafish 1(4):363-8.
Poleo G, Brown CW, Laforest L, Akimenko MA. 2001. Cell proliferation and movement during early fin regeneration in zebrafish. Dev Dyn 221(4):380-90.
Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA. 2011. Transient regenerative potential of the neonatal mouse heart. Science 331(6020):1078-80.
Poss KD. 2007. Getting to the heart of regeneration in zebrafish. Semin Cell Dev Biol 18(1):36-45.
Poss KD, Wilson LG, Keating MT. 2002. Heart regeneration in zebrafish. Science 298(5601):2188-90.
Ptaszek LM, Mansour M, Ruskin JN, Chien KR. 2012. Towards regenerative therapy for cardiac disease. Lancet 379(9819):933-42.
Rasmussen TL, Raveendran G, Zhang J, Garry DJ. 2011. Getting to the heart of myocardial stem cells and cell therapy. Circulation 123(16):1771-9.
Rawls JF, Mellgren EM, Johnson SL. 2001. How the zebrafish gets its stripes. Dev Biol 240(2):301-14.
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R et al. . 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58(1):32-45.
Reichenbach DD, Moss NS, Meyer E. 1977. Pathology of the heart in sudden cardiac death. Am J Cardiol 39(6):865-72.
Rhen T, Cidlowski JA. 2005. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 353(16):1711-23.
Rombough PJ. 2007. Ontogenetic changes in the toxicity and efficacy of the anaesthetic MS222 (tricaine methanesulfonate) in zebrafish (Danio rerio) larvae. Comp Biochem Physiol A Mol Integr Physiol 148(2):463-9.
Rotman M, Wagner GS, Wallace AG. 1972. Bradyarrhythmias in acute myocardial infarction. Circulation 45(3):703-22.
Ryan S. 1992. The dynamics of MS-222 anaesthesia in a marine teleost (Pagrus auratus: Sparidae). Comp Biochem Physiol C 101(3):593-600.
Ryan SN, Davie PS, Gesser H, Wells RMG. 1993. The effect of MS-222 on paced ventricle strips and the perfused heart of rainbow trout, Oncorhyncus mykiss. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology 106(2):549-553.
Sedmera D, Reckova M, deAlmeida A, Sedmerova M, Biermann M, Volejnik J, Sarre A, Raddatz E, McCarthy RA, Gourdie RG et al. . 2003. Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol 284(4):H1152-60.
Seibert K, Masferrer J, Zhang Y, Gregory S, Olson G, Hauser S, Leahy K, Perkins W, Isakson P. 1995. Mediation of inflammation by cyclooxygenase-2. Agents Actions Suppl 46:41-50.
Shafer SL, Hendrickx JF, Flood P, Sonner J, Eger EI, 2nd. 2008. Additivity versus synergy: a theoretical analysis of implications for anesthetic mechanisms. Anesth Analg 107(2):507-24.
Shafizadeh E, Huang H, Lin S. 2002. Transgenic Zebrafish Expressing Green Fluorescent Protein. p. 225-234.
Siekmann AF, Lawson ND. 2007. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445(7129):781-4.
Singer AJ, Clark RA. 1999. Cutaneous wound healing. N Engl J Med 341(10):738-46.
Song Y, Cone RD. 2007. Creation of a genetic model of obesity in a teleost. FASEB J 21(9):2042-9.
Soria G, Ofri-Shahak M, Haas I, Yaal-Hahoshen N, Leider-Trejo L, Leibovich-Rivkin T, Weitzenfeld P, Meshel T, Shabtai E, Gutman M et al. . 2011. Inflammatory mediators in breast cancer: coordinated expression of TNFalpha & IL-1beta with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition. BMC Cancer 11:130.
Sousa S, Afonso N, Bensimon-Brito A, Fonseca M, Simoes M, Leon J, Roehl H, Cancela ML, Jacinto A. 2011. Differentiated skeletal cells contribute to blastema formation during zebrafish fin regeneration. Development 138(18):3897-905.
Steinhauser ML, Lee RT. 2011. Regeneration of the heart. EMBO Mol Med 3(12):701-12.
Stoletov K, Fang L, Choi SH, Hartvigsen K, Hansen LF, Hall C, Pattison J, Juliano J, Miller ER, Almazan F et al. . 2009. Vascular lipid accumulation, lipoprotein oxidation, and macrophage lipid uptake in hypercholesterolemic zebrafish. Circ Res 104(8):952-60.
Sun J, Li SH, Liu SM, Wu J, Weisel RD, Zhuo YF, Yau TM, Li RK, Fazel SS. 2009a. Improvement in cardiac function after bone marrow cell thearpy is associated with an increase in myocardial inflammation. Am J Physiol Heart Circ Physiol 296(1):H43-50.
Sun P, Zhang Y, Yu F, Parks E, Lyman A, Wu Q, Ai L, Hu CH, Zhou Q, Shung K et al. . 2009b. Micro-electrocardiograms to study post-ventricular amputation of zebrafish heart. Ann Biomed Eng 37(5):890-901.
Sun X, Hoage T, Bai P, Ding Y, Chen Z, Zhang R, Huang W, Jahangir A, Paw B, Li YG et al. . 2009c. Cardiac hypertrophy involves both myocyte hypertrophy and hyperplasia in anemic zebrafish. PLoS One 4(8):e6596.
Tang A, Gilchrest BA. 1996. Regulation of keratinocyte growth factor gene expression in human skin fibroblasts. J Dermatol Sci 11(1):41-50.
Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, Phillips MI. 2005. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg 80(1):229-36; discussion 236-7.
Thomas PD, Kejariwal A, Campbell MJ, Mi H, Diemer K, Guo N, Ladunga I, Ulitsky-Lazareva B, Muruganujan A, Rabkin S et al. . 2003. PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res 31(1):334-41.
Tran TC, Sneed B, Haider J, Blavo D, White A, Aiyejorun T, Baranowski TC, Rubinstein AL, Doan TN, Dingledine R et al. . 2007. Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer Res 67(23):11386-92.
Traver D, Winzeler A, Stern HM, Mayhall EA, Langenau DM, Kutok JL, Look AT, Zon LI. 2004. Effects of lethal irradiation in zebrafish and rescue by hematopoietic cell transplantation. Blood 104(5):1298-305.
Tsai LY, Tseng SH, Yeh SR. 2005. Long-lasting potentiation of excitatory synaptic signaling to the crayfish lateral giant neuron. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191(4):347-54.
van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J. 2010. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7(1):30-7.
Wallner BP, Mattaliano RJ, Hession C, Cate RL, Tizard R, Sinclair LK, Foeller C, Chow EP, Browing JL, Ramachandran KL et al. . 1986. Cloning and expression of human lipocortin, a phospholipase A2 inhibitor with potential anti-inflammatory activity. Nature 320(6057):77-81.
Westerfield M. 1993. The Zebrafish book : a guide for the laboratory use of zebrafish (Brachydanio rerio). Eugene. Or.: University of Oregon Press.
White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE et al. . 2008. Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell 2(2):183-9.
Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, Smith SF, North P, Callaway H, Kelly K et al. . 2005. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3(1):e7.
Xu W, Zhang X, Qian H, Zhu W, Sun X, Hu J, Zhou H, Chen Y. 2004. Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med (Maywood) 229(7):623-31.
Zareba W. 2007. Drug induced QT prolongation. Cardiol J 14(6):523-33.

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