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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 周涵怡 | |
dc.contributor.author | Li-Yu Chen | en |
dc.contributor.author | 陳立瑜 | zh_TW |
dc.date.accessioned | 2021-05-14T17:42:51Z | - |
dc.date.available | 2015-09-24 | |
dc.date.available | 2021-05-14T17:42:51Z | - |
dc.date.copyright | 2015-09-24 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-13 | |
dc.identifier.citation | Study I
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Lin, Surface characterization and in vitro platelet compatibility study of surface sulfonated chitosan membrane with amino group protection-deprotection strategy. J Biomater Sci Polym Ed, 2008. 19(3): p. 291-310. 15. Chen, Y.H., et al., Control of cell attachment on pH-responsive chitosan surface by precise adjustment of medium pH. Biomaterials, 2012. 33(5): p. 1336-42. 16. Chen, Y.H., et al., Cell fractionation on pH-responsive chitosan surface. Biomaterials, 2013. 34(4): p. 854-63. 17. Chu, Y.W., et al., Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol, 1997. 17(3): p. 353-60. Study II 1. Mehlen, P. and A. Puisieux, Metastasis: a question of life or death. Nat Rev Cancer, 2006. 6(6): p. 449-58. 2. Stewart, B.W., et al., World cancer report 2014. xiv, 630 pages. 3. Jemal, A., et al., Cancer statistics, 2004. CA Cancer J Clin, 2004. 54(1): p. 8-29. 4. Mazzone, P., et al., Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer. Clin Chest Med, 2002. 23(1): p. 137-58, ix. 5. Velve-Casquillas, G., et al., Microfluidic tools for cell biological research. Nano Today, 2010. 5(1): p. 28-47. 6. Velve Casquillas, G., et al., Fast microfluidic temperature control for high resolution live cell imaging. Lab Chip, 2011. 11(3): p. 484-9. 7. Velve-Casquillas, G., et al., A fast microfluidic temperature control device for studying microtubule dynamics in fission yeast. Methods Cell Biol, 2010. 97: p. 185-201. 8. Forry, S.P. and L.E. Locascio, On-chip CO2 control for microfluidic cell culture. Lab Chip, 2011. 11(23): p. 4041-6. 9. Lu, P., V.M. Weaver, and Z. Werb, The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol, 2012. 196(4): p. 395-406. 10. Cox, T.R. and J.T. Erler, Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech, 2011. 4(2): p. 165-78. 11. Jia, D., et al., Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer, 2010. 10: p. 364. 12. Sun, X., et al., The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin alpha9beta1-mediated activation of PI3-K/AKT and Erk1/2. Carcinogenesis, 2014. 35(1): p. 184-91. 13. Quail, D.F. and J.A. Joyce, Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013. 19(11): p. 1423-37. 14. Yeh, H.Y. and J.C. Lin, Surface characterization and in vitro platelet compatibility study of surface sulfonated chitosan membrane with amino group protection-deprotection strategy. J Biomater Sci Polym Ed, 2008. 19(3): p. 291-310. 15. Chen, Y.H., et al., Control of cell attachment on pH-responsive chitosan surface by precise adjustment of medium pH. Biomaterials, 2012. 33(5): p. 1336-42. 16. Chen, Y.H., et al., Cell fractionation on pH-responsive chitosan surface. Biomaterials, 2013. 34(4): p. 854-63. 17. Chu, Y.W., et al., Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol, 1997. 17(3): p. 353-60. 18. American Diabetes, A., Diagnosis and classification of diabetes mellitus. Diabetes Care, 2011. 34 Suppl 1: p. S62-9. 19. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes, 1979. 28(12): p. 1039-57. 20. Daneman, D., Type 1 diabetes. Lancet, 2006. 367(9513): p. 847-58. 21. Butler, A.E., et al., Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 2003. 52(1): p. 102-10. 22. American Diabetes, A., Standards of medical care in diabetes--2014. Diabetes Care, 2014. 37 Suppl 1: p. S14-80. 23. Krupp, M.A., et al., Current medical diagnosis & treatment. McGraw-Hill Companies: New York etc. ,. p. v. 24. Diabetes care. Med Econ, 2004. 81(17): p. 14, 16. 25. Jiang, Y.D., et al., Incidence and prevalence rates of diabetes mellitus in Taiwan: analysis of the 2000-2009 Nationwide Health Insurance database. J Formos Med Assoc, 2012. 111(11): p. 599-604. 26. Seino, S. and G.I. Bell, Pancreatic beta cell in health and disease. 2008, Tokyo: Springer. xv, 474 p. 27. Ma, L., et al., Direct imaging shows that insulin granule exocytosis occurs by complete vesicle fusion. Proc Natl Acad Sci U S A, 2004. 101(25): p. 9266-71. 28. Ammala, C., et al., Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells. J Physiol, 1993. 472: p. 665-88. 29. Rorsman, P. and E. Renstrom, Insulin granule dynamics in pancreatic beta cells. Diabetologia, 2003. 46(8): p. 1029-45. 30. Neher, E., Vesicle pools and Ca2+ microdomains: new tools for understanding their roles in neurotransmitter release. Neuron, 1998. 20(3): p. 389-99. 31. Parsons, T.D., et al., Docked granules, the exocytic burst, and the need for ATP hydrolysis in endocrine cells. Neuron, 1995. 15(5): p. 1085-96. 32. Gromada, J., et al., CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells. J Physiol, 1999. 518 ( Pt 3): p. 745-59. 33. Barg, S., et al., Fast exocytosis with few Ca(2+) channels in insulin-secreting mouse pancreatic B cells. Biophys J, 2001. 81(6): p. 3308-23. 34. Rorsman, P., et al., The Cell Physiology of Biphasic Insulin Secretion. News Physiol Sci, 2000. 15: p. 72-77. 35. Olofsson, C.S., et al., Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells. Pflugers Arch, 2002. 444(1-2): p. 43-51. 36. Cheng, K., S. Andrikopoulos, and J.E. Gunton, First phase insulin secretion and type 2 diabetes. Curr Mol Med, 2013. 13(1): p. 126-39. 37. Seino, S., T. Shibasaki, and K. Minami, Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J Clin Invest, 2011. 121(6): p. 2118-25. 38. Wang, Z., et al., Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal. FEBS Lett, 1999. 453(1-2): p. 135-9. 39. Horike, N., et al., Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem, 2003. 278(20): p. 18440-7. 40. Lin, X., et al., SIK (Salt-inducible kinase): regulation of ACTH-mediated steroidogenic gene expression and nuclear/cytosol redistribution. Endocr Res, 2000. 26(4): p. 995-1002. 41. Jhala, U.S., et al., cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev, 2003. 17(13): p. 1575-80. 42. Screaton, R.A., et al., The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell, 2004. 119(1): p. 61-74. 43. Muraoka, M., et al., Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1alpha and UCP-1 gene expression in brown adipocytes. Am J Physiol Endocrinol Metab, 2009. 296(6): p. E1430-9. 44. Park, J., et al., SIK2 is critical in the regulation of lipid homeostasis and adipogenesis in vivo. Diabetes, 2014. 63(11): p. 3659-73. 45. Sasaki, T., et al., SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron, 2011. 69(1): p. 106-19. 46. Horike, N., et al., Downregulation of SIK2 expression promotes the melanogenic program in mice. Pigment Cell Melanoma Res, 2010. 23(6): p. 809-19. 47. Ahmed, A.A., et al., SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell, 2010. 18(2): p. 109-21. 48. Fu, A., C.E. Eberhard, and R.A. Screaton, Role of AMPK in pancreatic beta cell function. Mol Cell Endocrinol, 2013. 366(2): p. 127-34. 49. Sakamaki, J., et al., Role of the SIK2-p35-PJA2 complex in pancreatic beta-cell functional compensation. Nat Cell Biol, 2014. 16(3): p. 234-44. 50. Henriksson, E., et al., The AMPK-related kinase SIK2 is regulated by cAMP via phosphorylation at Ser358 in adipocytes. Biochem J, 2012. 444(3): p. 503-14. 51. Speidel, D., et al., CAPS1 regulates catecholamine loading of large dense-core vesicles. Neuron, 2005. 46(1): p. 75-88. 52. Cisternas, F.A., et al., Cloning and characterization of human CADPS and CADPS2, new members of the Ca2+-dependent activator for secretion protein family. Genomics, 2003. 81(3): p. 279-91. 53. Khodthong, C., et al., Munc13 homology domain-1 in CAPS/UNC31 mediates SNARE binding required for priming vesicle exocytosis. Cell Metab, 2011. 14(2): p. 254-63. 54. Nguyen Truong, C.Q., et al., Secretory vesicle priming by CAPS is independent of its SNARE-binding MUN domain. Cell Rep, 2014. 9(3): p. 902-9. 55. Parsaud, L., et al., Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. J Biol Chem, 2013. 288(32): p. 23050-63. 56. Speidel, D., et al., A family of Ca2+-dependent activator proteins for secretion: comparative analysis of structure, expression, localization, and function. J Biol Chem, 2003. 278(52): p. 52802-9. 57. Binda, A.V., N. Kabbani, and R. Levenson, Regulation of dense core vesicle release from PC12 cells by interaction between the D2 dopamine receptor and calcium-dependent activator protein for secretion (CAPS). Biochem Pharmacol, 2005. 69(10): p. 1451-61. 58. Shinoda, Y., et al., Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network. Proc Natl Acad Sci U S A, 2011. 108(1): p. 373-8. 59. Sadakata, T., et al., Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest, 2007. 117(4): p. 931-43. 60. Liu, Y., et al., CAPS facilitates filling of the rapidly releasable pool of large dense-core vesicles. J Neurosci, 2008. 28(21): p. 5594-601. 61. Neuman, J.C., et al., A method for mouse pancreatic islet isolation and intracellular cAMP determination. J Vis Exp, 2014(88): p. e50374. 62. Berwin, B., E. Floor, and T.F. Martin, CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis. Neuron, 1998. 21(1): p. 137-45. 63. Sadakata, T., M. Washida, and T. Furuichi, Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants. BMC Neurosci, 2007. 8: p. 25. 64. Caromile, L.A., et al., The neurosecretory vesicle protein phogrin functions as a phosphatidylinositol phosphatase to regulate insulin secretion. J Biol Chem, 2010. 285(14): p. 10487-96. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4512 | - |
dc.description.abstract | 研究一 活細胞分析式微流道晶片之開發及其應用於癌症轉移潛能診斷之評估
摘要 肺癌的轉移若及早發現並加以治療,便能顯著提升患者改善病情的機會。然而,現行臨床癌症檢驗之方式,如胸腔攝影、斷層掃描及組織切片等,均未能有效判斷肺癌細胞轉移之可能性,以致患者無法獲得適當的治療。本研究中,吾人設計開發出一新型微流道晶片系統,以期作為快速評估癌症轉移潛能之臨床檢驗。本系統設計係以恆定環境溫度及酸鹼度為基礎,再以甲殼素附著之微流道表面偵測目標細胞之貼附性,作為判斷細胞遷移特性之依據。於實際測試中,吾人將不同轉移潛能之肺癌細胞株,經標定後以本系統進行細胞貼附性測試。結果顯示本系統確能有效區分不同轉移潛能之肺癌細胞株。因此,透過本系本研究所開發之微流道系統,僅需少量自患者經活體採樣分離之細胞樣本,便能迅速取得評估癌細胞轉移潛能之資訊。此微流道系統未來若能應用於臨床診斷,便能為肺癌及其他癌症患者,於早期研判適合之治療模式。 研究二 SIK2藉由磷酸化CAPS2調控胰島素分泌之探討 摘要 動物體的各種器官之協同運作,需仰賴內分泌系統對細胞之調節作用。胰島素即係一種負責控制血糖濃度之內泌素。當胰島素的生成或分泌發生異常,抑或是體內細胞出現胰島素失敏之現象,便可能引起糖尿病。佔總糖尿病患數90 – 95%之第二型糖尿病,其起因爲體細胞逐漸產生胰島素抗性,進而造成胰島素過量分泌之代償作用,終而導致β 細胞劇烈死亡。因此,改善其病徵之方法可為刺激胰島素分泌及抑制β 細胞凋亡。Salt inducible kinase 2 (SIK2) 係一屬AMPK族群之酵素,於β 細胞中調控胰島素之分泌,並藉由抑制CREB-mediated IRS-2基因表現,促使β 細胞凋亡。本研究室先前研究指出,SIK2可透過其磷酸酶活性控制β 細胞中胰島素小泡之遷移及分泌,而抑制SIK2磷酸酶活性可增加胰島素之分泌。為進一步探討SIK2對胰島素分泌調控之機轉,吾人以Scansite網站資料庫預測,發現calcium-dependent activator protein for secretion 2 (CAPS2) 蛋白具有SIK2之磷酸化目標序列,可能為SIK2之下游調控因子。欲了解SIK2是否會透過CAPS2影響胰島素分泌,本研究首先確認SIK2及CAPS2均於β 細胞中表現,再以免疫沈澱法驗證其交互作用,並以in vitro kinase assay證明CAPS2確為SIK2之磷酸化目標。然而,吾人實驗結果亦顯示於SIK2及CAPS2共同過量之小鼠β 細胞中,SIK2可透過CAPS2強化細胞對葡萄糖刺激之反應。綜合上述,本研究結果指出SIK2可藉磷酸化CAPS2調控β細胞中胰島素之分泌,然其中詳細之分子機制,尚待未來進一步研究發掘。 | zh_TW |
dc.description.abstract | Study I: A portable microfluidic device for the rapid diagnosis of cancer metastatic potential which is programmable for temperature and CO2
Abstract If metastasis of lung cancer can be found and treated early, a patient might have an improved chance to prevail over it, but routine examinations such as chest radiography, computed tomography and biopsy cannot characterize the metastatic potential of lung cancer cells; critical diagnoses to define optimal therapeutic strategies are thus lost. In this study, we designed a portable microfluidic device for the rapid diagnosis of cancer metastatic potential. Featuring a micro system to control temperature and a bicarbonate buffered environment, our device discriminates a rate of surface detachment as an index of the migratory ability of cells cultured on pH-responsive chitosan. We labeled metastatic subpopulations of lung cancer cell lines, and verified that our device is capable of separating cells according to their metastatic ability. As only few cells are needed, a patient's specimen from biopsies, e.g. from fine-needle aspiration, can be processed on site to offer immediate information to physicians. We expect that our design will provide valuable information in pre-operative evaluations to assist the definition of therapeutic plans for lung cancer, as well as for metastatic tumors of other types. Study II: Identification of CAPS2 as a downstream target of SIK2 in regulating insulin secretion Abstract Through the endocrine system, communications between cells in various tissues in our body are well coordinated to drive a variety of physiological events properly. Insulin, one of endocrines, is secreted in response to elevated blood concentration of glucose, thereby keeps blood sugar level within certain range. Either failures of production and secretion of insulin, or cellular insulin insensitivity could result in diabetes mellitus. Type 2 diabetes (T2D) accounting for 90–95% of those with diabetes, is caused by the cellular resistance to insulin stimulation which leads to progressive insulin secretion defect in order to compensate for the less responsive reactions, and finally massive death of β cells. Ways to treat T2D are to stimulate more insulin secretion and to inhibit β cell death. Salt inducible kinase 2 (SIK2), a member of AMPK family, plays important roles in both β cell survival as well as insulin secretion. SIK2 has been reported to suppress β cell survival by repressing CREB-mediated IRS-2 gene expression. Our group found that SIK2 is expressed in insulin-producing β cells and regulates dynamics of insulin secretion via its kinase activity. Inhibition of SIK2 kinase activity resulted in vesicle mobilization to the membrane and increased insulin release. To further understand the machinery of the regulation of insulin secretion by SIK2, we applied Scansite database search program and found that CAPS2 (calcium-dependent activator protein for secretion 2), the vesicle related protein containing SIK2 phosphorylation consensus motif, was considered as a putative downstream substrate of SIK2. Herein, we firstly confirmed the physiological protein interaction between CAPS2 and SIK2, and found the interaction was correlated to SIK2 kinase activity. In addition, our in vitro kinase assay results provide clear evidences to show that CAPS2 is the direct substrate of SIK2. However, in SIK2/CAPS2 overexpressing mouse primary β cells, SIK2 might regulate insulin secretion via CAPS2 by sensitizing the responses to glucose in β cells. Taken together, our findings suggest that the function of CAPS2 is involved in insulin secretion and is regulated by protein kinase SIK2. Future studies are needed to reveal the mechanisms of the SIK2/CASP2 pathway in controlling insulin secretion. | en |
dc.description.provenance | Made available in DSpace on 2021-05-14T17:42:51Z (GMT). No. of bitstreams: 1 ntu-104-R02450006-1.pdf: 30089731 bytes, checksum: 1280a638e697c98c3f4b22be2c1a9cd0 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 研究一 活細胞分析式微流道晶片之開發及其應用於癌症轉移潛能診斷之評估 1
摘要 1 Study I: A portable microfluidic device for the rapid diagnosis of cancer metastatic potential which is programmable for temperature and CO2 2 Abstract 2 Background 3 Lung cancer, the foremost cause of cancer related deaths 3 Routine examinations for lung cancer and its limitations 4 Aim 6 Design 7 Design Concept 7 Microfluidic chip as a principle part of device 7 Microfluidic cell culture 8 Metastatic index 9 Analytic platform 10 Materials and methods 13 Microfluidic fabrication 13 Chitosan preparation and coating 14 Cell Culture 14 Cell migration and proliferation measurement 15 Fluorescenct reagent and staining 15 Cell seeding and detachment assays on MD-CaMP 17 Cell seeding and attachment assays on culture dish 17 Western blot analysis 18 Results 19 Design of MD-CaMP 19 Migratory abilities of CL1-0, CL1-1 and CL1-5 Cell model for MD-CaMP testing 20 Fibronectin expression of CL1-0, CL1-1,CL1-5 21 Correlation of metastatic potential with rate of detachment on chitosan 22 Selective fractionation of cells from a mixed population by their differential rate of detachment 24 Altered cell morphology with pH 25 Differential attaching properties of CL1-0, CL1-1 and CL1-5 on chitosan surface 25 Cell fractionation of co-cultured CL1-0, CL1-1, CL1-5 by differential attachment properties on chitosan surface 27 Conclusion and Discussion 29 Reference 33 Figures 34 Appendix 43 研究二 SIK2藉由磷酸化CAPS2調控胰島素分泌之探討 44 摘要 44 Study II: Identification of CAPS2 as a downstream target of SIK2 in regulating insulin secretion 45 Abstract 45 Introduction 47 Definition, classification, cause and prevalence of diabetes mellitus 47 Secretory pathway, distinct pools and biphasic secretion of insulin vesicles in pancreatic β cells 48 Roles of SIK2 in metabolism and insulin function 51 The expression and function of SIK2 in pancreatic β cell in regulating insulin secretion 53 CAPS2 as a putative substrate of SIK2 in regulation of insulin secretion 55 Aim 58 Materials and Methods 59 Isolation of pancreatic islets 59 Antibodies 60 Immunofluorescent staining: 60 RNA isolation and RT-PCR 62 Cloning of full length CAPS2 62 Site direct mutagenesis of pCMV-myc-CAPS2(1-1260) 65 SIK2 constructs 66 Transfection 66 Immunoprecipitation 67 In vitro kinase assay 67 Western blot analysis 68 Insulin ELISA 68 Results 70 The expression of SIK2 and CAPS2 in mouse pancreatic islets 70 Subcellular localization of SIK2 and CAPS2 in mouse pancreatic β cell 70 Cloning of β cells expressed CAPS2 isoform 71 Physiological relevant proteins interaction between SIK2 and CAPS2 73 Putative SIK2 phosphorylation sites on CAPS2 and CAPS2-MUT-T1016A, T1052A, T1231A construct 74 In vitro phosphorylation of SIK2 on CAPS2 75 Transfection and expression of pTimer-phogrin in primarily cultured islet cells 76 Insulin secretion of SIK2/CAPS2 overexpressed mouse primary β cells 77 Conclusion and Discussion 80 References 85 Figures 89 | |
dc.language.iso | en | |
dc.title | 活細胞分析式微流道晶片之開發及其應用於癌症轉移潛能診斷之評估暨
SIK2藉由磷酸化CAPS2調控胰島素分泌之探討 | zh_TW |
dc.title | Study I: A portable microfluidic device for the rapid diagnosis of cancer metastatic potential
Study II: Identification of CAPS2 as a downstream target of SIK2 in regulating insulin secretion | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 許聿翔,宋麗英 | |
dc.subject.keyword | 微流道,生物晶片,肺癌,癌症轉移,胰島素,糖尿病,磷酸化, | zh_TW |
dc.subject.keyword | Microfluidics,Biochip,Lung cancer,Metastasis,Insulin,Diabetes,Phosphorylation, | en |
dc.relation.page | 106 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2015-08-14 | |
dc.contributor.author-college | 牙醫專業學院 | zh_TW |
dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
顯示於系所單位: | 口腔生物科學研究所 |
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