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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 王致恬(Chih-Tien Wang) | |
dc.contributor.author | Hsin-I Jen | en |
dc.contributor.author | 任心怡 | zh_TW |
dc.date.accessioned | 2021-06-15T06:46:36Z | - |
dc.date.available | 2016-07-06 | |
dc.date.copyright | 2011-07-06 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-06-16 | |
dc.identifier.citation | Aihara H, Miyazaki J (1998) Gene transfer into muscle by electroporation in vivo. Nat Biotechnol 16:867-870.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48116 | - |
dc.description.abstract | 催產素和血管加壓素在許多動物行為中扮演了重要的調控角色,其分泌來源以及功能受到廣泛的研究。我們已知視上核為分泌此兩種荷爾蒙的來源之一,其內部神經細胞可利用軸突及樹突,分別將包覆於緻密核心囊內的催產素和血管加壓素分泌至血液以及腦脊髓液中,但是分泌的機制仍未明瞭。為了釐清此機制,我們首先利用活體電穿孔技術將不同囊泡相關蛋白,包括Synaptotagmin I、IV(Syt I & Syt IV) 以及Syanpsin Ia (Syn Ia) 轉染至大鼠視上核內。Syt I、IV皆為鈣離子感測蛋白,可調控緻密核心囊泡的分泌量以及分泌速度;而Syn Ia為一種可磷酸化蛋白,研究指出其具有調控突觸囊泡與機動蛋白束互動的能力,近來更進一步了解Syn Ia也可以影響緻密核心囊泡的分泌。
在本篇研究中,首先藉由免疫螢光染色,我們證明利用活體電穿孔技術可成功將目標蛋白大量表現在視索上核內。接著,為了觀察此兩種蛋白對於囊泡分泌的機制,我們使用電子顯微鏡觀察緻密核心內囊泡的直徑以及囊泡與細胞膜間距離的改變,同時也利用酵素連結免疫吸附試驗,來觀察血液與腦脊髓液內催產素與血管加壓素的含量,在大量表現不同目標蛋白時有何影響。結果顯示:第一、Syn Ia參與了正向調控腦部受損時血管加壓素的分泌。第二、於視上核大量表現Syt IV不影響血液內催產素含量,卻降低了血液中血管加壓素含量,因此催產素與血管加壓素分泌至血液的調控機制並不相同。第三、於視上核大量表現Syt IV,其軸突分泌至血液內的催產素含量並未改變,但其樹突分泌至腦脊液的催產素含量卻明顯增加,由此可知軸突和樹突也是利用不同調控機制分泌催產素。 最後,我們也發現同時大量表現Syt IV與Syn Ia的點突變蛋白,會導致緻密核心囊泡大量聚集、縮短囊泡與細胞膜間距離以及降低催產素和血管加壓素的分泌量。我們的結果顯示,軸突和樹突是利用不同調控機制分泌催產素且,催產素與血管加壓素分泌至血液的調控機制並不相同。Syt IV與Syn Ia兩者相互作用參與了調控視上核催產素與血管加壓素的釋放機制。 | zh_TW |
dc.description.abstract | Oxytocin (OT) and vasopressin (VP) are hormones involved in the regulation of a wide variety of behaviors. The effects and release origins of these hormones have been well documented; however, release mechanisms are still elusive. One of the release origins of these hormones is the supraoptic nucleus (SON). In the SON neurons, the OT and VP, enclosed in the dense cored vesicles (DCVs), undergo both axonal release and somatodendritic release into blood and cerebrospinal fluid (CSF), respectively. The release mechanisms are still unclear. To resolve these questions, we overexpressed several vesicle proteins in the SON to study the roles underlying OT and VP release. First, we used newly developed in vivo electroporation technique to transfect various vesicle proteins, i.e. Synaptotagmin I , IV (Syt I & Syt IV), and synapsin Ia (Syn Ia), in the SON region of adult male Sprague-Dawley (SD) rats. Syt I and Syt IV are vesicle proteins acting as Ca2+ sensor in regulated exocytosis that has been found to regulate the kinetics of DCV release recently. Syn Ia, a phosphoprotein that controls synaptic vesicle association with actin filaments, has been reported to regulate DCV release.
In this study, we first used immunoflourescence staining to confirm that these vesicle proteins can be successfully overexpressed in the SON region by in vivo electroporation. Second, we used electron microscopy (EM) to further study the morphological changes of the vesicles. We analyzed the vesicle size and the vesicular distance to plasma membrane in each transfected group. Third, to determine the physiological roles of these vesicle proteins, we applied the enzyme-linked immunosorbent assay (ELISA) to measure the changes of OT and VP concentration in plasma and cerebrospinal fluid (CSF), which reflect axonal and somatodendritic release, respectively. We found that Syn Ia increased OT and VP release into blood, and also increased OT release into CSF, suggesting that Syn Ia plays as a positive regulator in both axonal and somatodendritic release. In contrast, Syt IV overexpression in the SON region did not change the OT release into blood, but decreased the VP release into blood, indicating that Syt IV plays as a negative regulator in VP axonal release. Thus, the molecular mechanisms underlying OT and VP release from axonal terminals may be different. Moreover, Syt IV overexpression in the SON region increased the OT release into CSF, but rather into blood, suggesting that Syt IV plays as a positive regulator in OT somatodendritic release. Since Syt IV did not change OT axonal release but regulate OT somatodendritic release positively, these results indicated that different molecular mechanisms may be required for axonal release and somatodendritic release. Lastly, overexpressing Syt IV along with Syn Ia mutant (S62A) in the SON region resulted in vesicle cluster formation, and decreased both axonal and somatodendritic release for OT and VP to blood and CSF. These results suggest that the positive role of Syn Ia in axonal and somatodendritic release of these two neuropeptides may be through phosphorylation of the residue at S62. Moreover, Syn Ia may affect neuropeptide axonal and somatodendritic release by interacting with the molecular components in DCVs, such as Syt IV. In conclusion, our study provided some clues for different mechanisms underlying axonal and somatodendritic release for OT and VP. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:46:36Z (GMT). No. of bitstreams: 1 ntu-100-R98b43015-1.pdf: 10645496 bytes, checksum: 7e32edb490e5bbf4a57b2f419e4b2262 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Contents
口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract v Abbreviations vii Contents x Chapter I Introduction 1 1 Ca2+-Regulated Exocytosis 1 1.1 Types of Vesicles in Ca2+-Regulated Exocytosis 1 1.2 Molecular Mechanism of Ca2+-Regulated Exocytosis 2 1.2.1 Synaptotagmin 3 1.2.1.1 Syt Structure and Isoforms 4 1.2.1.2 Syt I 4 1.2.1.3 Syt IV 5 1.2.2 Synapsin 6 2 A Model to Study Neuropeptide Release – Hypothalamic-Neurohypophysial System 8 2.1 Supraoptic Nucleus 8 2.2 Oxytocin 10 2.3 Vasopressin 10 2.3 Behavioral Effects of OT and VP 11 3 In Vivo Electroporation 11 4 The Purpose of This Study 12 Chapter II Materials and Methods 13 1 Animals 13 2 Molecular Biology 13 3 Homemade Electrodes 14 4 Stereotactic Surgery and In Vivo Electroporation 14 5 Transcardiac Perfusion 16 6 Cryosection 17 7 Immunofluorescence Staining 18 8 Acquisition of Plasma and Cerebrospinal Fluid (CSF) 19 9 Enzyme-Linked Immunosorbent Assay (ELISA) 20 10 Electron Microscope (EM) 21 10.1 Sample Preparation 21 10.2 Dehydration 22 10.3 Embedding 22 10.4 Sectioning 22 10.5 Contrast Staining 24 10.6 Data Analysis for EM 24 11 Statistics in This Thesis 24 Chapter III Results 26 1. Protein expression patterns 26 1.1 Supraoptic Nucleus (SON) were recognized by immunofluorescence staining of oxytocin (OT) and vasopressin (VP) 26 1.2 Syt I, Syt IV and Syn Ia were expressed differently in the SON 26 1.3 Syn Ia was partially expressed in the soma and fibers of both oxytocinergic and vasopressinergic neurons 27 1.4 Genes of interest can be successfully delivered, transfected and overexpressed in the SON 28 1.5 Syt IV can be successfully overexpressed in the Oxytocinergic and vasopressinergic neurons 29 1.6 Syt IV & Syn Ia* caused clustered vesicles in the SON 29 1.7 The vesicle size of SON neurons varied after in vivo electroporation 30 2. Mechanisms and morphology changed after transfection - EM 31 2.1 Overexpressing Syn Ia decreased the vesicle size of SON neurons 31 2.2 Two populations of vesicles present in the SON neurons 32 2.3 Overexpressing Syt I, Syt IV and Syn Ia decreased the proportion of SDCVs in SON neurons 32 2.4 The in vivo electroporation significantly increased the size of SDCVs and LDCVs 33 2.5 Overexpressing Syn Ia* significantly reduced the size of SDCVs compared to in vivo electroporation alone (S.C.) 34 2.6 Overexpression of Syt I, Syt IV, Syn Ia, Syn Ia* and Syt IV& Syn Ia* increased the size of LDCVs compared to S.C. 35 2.7 Overexpressing Syt I conferred larger SDCVs and smaller LDCVs compared to overexpressing Syt IV 35 2.8 The distance between the vesicle and plasma membrane varied after transfection of different genes 36 2.9 The distance between the vesicle and nuclear membranes varied after transfection of different genes 38 2.10 The vesicle location in the soma (Ratios of vesicle to plasma membranes / nuclear to plasma membranes) 39 2.11 Syt isoforms significantly decreased the average number of vesicles in the SON soma 40 3. Physiological changes after transfection – ELISA and body weight 41 3.1 The in vivo electroporation prevented the stress-dependent OT increase to plasma 41 3.2 Overexpression of Syn Ia in SON significantly increased the OT concentrations in plasma 42 3.3 Overexpression of Syt IV & Syn Ia* significantly decreased the OT plasma concentrations compared with overexpression of Syn Ia 43 3.4 The in vivo electroporation increased VP release to plasma 44 3.5 Overexpression of Syn Ia in SON significantly increased the VP concentrations in plasma 45 3.6 Overexpression of Syt IV, Syn Ia* and Syt IV & Syn Ia* significantly decreased the VP concentrations in plasma compared to in vivo electroporation alone (S.C.) 46 3.7 The in vivo electroporation did not change the mean OT concentration in CSF 48 3.8 Overexpression of Syt IV or Syn Ia in SON significantly increased the OT release to CSF, whereas overexpression of Syt IV & Syn Ia* significantly decreased the OT release to CSF 49 3.9 Overexpression of Syt IV and Synapsin Ia* significantly decreased the OT concentration in CSF by comparing different groups 50 3.10 In vivo electroporation did not change the body weight 51 3.11 Overexpression of Syt IV & Syn Ia significantly increased the body weight 52 Chapter IV Discussion 55 1. Syn Ia, not a DCV protein, influences DCV exocytosis 55 2. Some effects of Syn Ia are S62-dependent but others not 56 3. Syt IV expression may be modulated at translational level, and may not exclusively localize to the OT and VP-containing vesicles 56 4. Syt IV may function differently in OT axonal and somatodendritic release 57 5. Interaction between Syt IV and Syn Ia* 57 6. Stress increases OT release to plasma 58 7. Brain injury increases VP release to plasma 59 8. Syt IV act as a negative regulator in VP release to plasma in the injured brain, while Syn Ia as a positive regulator 59 9. Syt IV-containing vesicles may be under the control of Syn Ia 60 10. Proximity to plasma may not be a suitable indicator as release probability in this study 61 11. Body weight increased with Syt IV overexpression 62 12. OT and VP concentration on locomotor activity 62 13. Overexpressing Syt IV& Syn Ia* inhibits acoustic startle response 64 Chapter V Conclusion 66 References 67 List of Figures Figure 1 Synaptotagmin structure (Bhalla et al., 2008) 75 Figure 2 Molecular interaction of Synapsin (Firth et al., 2005) 76 Figure 3 Amperometric recordings from PC 12 cells overexpressing Synapsin Ia phosphorylation-defective mutant (Synapsin Ia-S62A) (Wang, 2001) 77 Figure 4 The SON in the HNS (Burbach et al., 2001) 78 Figure 5 OT and VP staining in SON and PVN (Ludwig and Leng, 2006) 79 Figure 6 Stereotaxic surgery and in vivo electroporation (Kao, 2011) 80 Figure 7 Changes in acoustic startle response after in vivo electroporation 81 Figure 8 Homemade electrodes for in vivo electroporation (Kao, 2011) 82 Figure 9 The location of SON 83 Figure 10 Syt I in the intact SON 84 Figure 11 Syt I in the SON transfected with Syt I by in vivo electroporation 85 Figure 12 Syt IV in the intact SON 86 Figure 13 Syt IV in the SON transfected with Syt IV by in vivo electroporation 87 Figure 14 Syn Ia in the intact SON 88 Figure 15 The Syn Ia in the SON transfected with Syn Ia by in vivo electroporation 89 Figure 16 Transfection efficiency and the overexpression level after in vivo electroporation 90 Figure 17 Syn Ia in oxytocinergic and vasopressinergic neurons 91 Figure 18 Syn Ia was not colocalized with the axonal marker (SMI 312) in the SON 92 Figure 19 Syn Ia was partially colocalized to OT and VP in the posterior pituitary (PP) 93 Figure 20 Syt IV overexpression targeted to both OT and VP neurons in the SON transfected with Syt IV 94 Figure 21 Syt IV in the SON co-transfected with Syt IV & Syn Ia* (S62A) 96 Figure 22 Somata of the SON neurons 97 Figure 23 Vesicle size of the SON neurons 98 Figure 24 Distribution of vesicle size in the SON neurons 99 Figure 25 Vesicle size for SDCVs and LDCVs of SON neurons 100 Figure 26 Distance between vesicle and the plasma membranes 101 Figure 27 Distribution of distance between vesicle and plasma membranes in the SON neurons 102 Figure 28 Distance between vesicle and the nuclear membranes 103 Figure 29 Distribution of distance between vesicle and nuclear membranes in the SON neurons 104 Figure 30 Location of vesicles in the cytosol of SON neurons 105 Figure 31 The vesicle number in the SON somata 106 Figure 32 OT concentration in the plasma 107 Figure 33 VP concentration in the plasma 108 Figure 34 OT concentration in the CSF 109 Figure 35 Body weight 110 Figure 36 The working model for OT and VP release in the SON 111 List of Tables Table 1 Antibodies for immunofluorescence staining 113 Table 2 Properties of DCVs according to Gaussian-fitted distributions 114 Table 3 Changes in OT and VP concentrations after in vivo electroporation 115 Table 4 In vivo electroporation in the HNS may affect vesicle parameters, neuropeptide release and animal behavior 116 Table 5 Overexpression of different vesicle proteins in the HNS may affect vesicle parameters, neuropeptide release and animal behavior 118 Table 6 Comparisons between transfected groups 119 Appendix Behavior 121 The 2010 annual meeting of the Society for Neuroscience (San Diego, CA, U.S.A.11/17-21/2010) poster 147 | |
dc.language.iso | en | |
dc.title | 利用活體電穿孔技術在下視丘-神經垂體系統中研究 Synaptotagmin 和 Synapsin Ia 對分泌催產素和血管加壓素所扮演的角色 | zh_TW |
dc.title | The Study of the Roles of Synaptotagmin and Synapsin Ia in the Oxytocin and Vasopressin Release from Hypothalamic-Neurohypophysial System by In Vivo Electroporation | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 徐立中(Li-Chung Hsu),王懷詩(Hwai-shi Wang),賴文崧(Wen-Sung Lai) | |
dc.subject.keyword | 突觸結合蛋白,催產素,血管加壓素,視上核,電穿孔,突觸蛋白, | zh_TW |
dc.subject.keyword | Synatotagmin,oxytocin,vasopressin,electroporation,supraoptic nucleus,synapsin, | en |
dc.relation.page | 147 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-06-21 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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