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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林璧鳳 | zh_TW |
| dc.contributor.advisor | Bi-Fong Lin | en |
| dc.contributor.author | 林雅莉 | zh_TW |
| dc.contributor.author | Alana Jr Ang Barretto | en |
| dc.date.accessioned | 2024-03-21T16:49:54Z | - |
| dc.date.available | 2024-03-22 | - |
| dc.date.copyright | 2024-03-21 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-01-22 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92369 | - |
| dc.description.abstract | 抑制性神經傳導物質γ-胺基丁酸（GABA）已被證明能夠緩解腎小管特定條件von Hippel-Lindau（VHL）基因敲除小鼠(Hoxb7-Cre-GFP/+; Vhlhfl/fl)或(Vhlhfl/fl)的腎臟發炎並增加壽命，這些小鼠自發性地發展出發炎和腎臟損傷。 這促使人們對神經抑制與免疫反應之間的相關性進行研究。
為了研究神經抑制與免疫反應之間的關係，將Vhlhfl/fl小鼠與野生型小鼠(Hoxb7-Cre-GFP/+; Vhlh+/fl or Hoxb7-GFP/-; Vhlhfl/fl 小鼠)進行比較 ，並在為期10週的時間裡餵食含有79.5g/kg GABA補充劑的AIN-93飲食。實驗中我們透過免疫組織化學染色法來觀察了腎臟神經形態。在動物模型的脾臟以及HEK-293和HK-2細胞系中，使用shVHL25和shVHL61基因敲除來評估發炎因子，這些基因以0 μM、250 μM以及500 μM 的 GABA來進行處理.。 數據顯示，VHL缺陷的動物以及細胞導致了他們的抗發炎細胞因子(IL-6, TNF-α, IFN-γ, IL-17A/F, TGF-β, and MCP-1) 、VHL 症狀標記 (HIF, EPO, and VEGF) 以及神經營養因子 (NGF and BDNF)的表現上升。然而GABA的補充都會導致抗發炎細胞因子、VHL症候標記以及神經營養因子的表現下降。值得注意的是，接受GABA處理的組別也表現出神經生長的減少，顯示GABA可能透過抑制神經生長來對抗腎臟損傷。該研究顯示了GABA在調節腎臟損傷背景下的免疫反應和神經調控方面的治療潛力。 | zh_TW |
| dc.description.abstract | The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) was shown to alleviate renal inflammation and increase lifespan of the renal tubule specific condition von Hippel-Lindau (VHL) gene knockout mice (Hoxb7-Cre-GFP/+; Vhlhfl/fl) or (Vhlhfl/fl) that spontaneously develop inflammation, and renal injury. Prompting investigations into the correlations between the neuronal inhibition and the immune response.
To study the correlation between neuronal inhibition and the immune response, Vhlhfl/fl mice were compared to the wild-type (Hoxb7-Cre-GFP/+; Vhlh+/fl or Hoxb7-GFP/-; Vhlhfl/fl mice) and fed AIN-93 diets containing 79.5g/kg of GABA supplementation for a 10-week period. Renal nerve morphology was assessed through 3-dimensional immunohistochemistry staining. Inflammatory factors were assessed in the spleen of the animal model as well as in vitro with the use of HEK-293 and HK-2 cell lines, featuring shVHL25 and shVHL61 gene knockdowns, that were treated with 0 μM, 250 μM, and 500 μM of GABA. Our data showed that VHL deficit animal and cell models resulted in an increase of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-17A/F, TGF-β, and MCP-1), VHL syndrome markers (HIF, EPO, and VEGF) and neurotropic factors (NGF and BDNF). Indicating the inflammatory response and early markers of angiogenesis. However, GABA supplementation resulted in a downregulation of this response. Notably, GABA-treated groups also exhibited a decrease in nerve growth, suggesting a potential mechanism through which GABA may confer protective effects against renal injury by suppressing nerve growth. This study underscores the therapeutic potential of GABA in modulating neuronal and immune regulation in renal injury. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-03-21T16:49:54Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-03-21T16:49:54Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 審定書 i
誌謝 ii 中文摘要 iii Abstract: iv CONTENTS v Figure List ix Table List xi Abbreviation Table xii Literature Review 1 1.1 Renal cancer and the pre-tumour microenvironment 1 1.1.1 Renal cancer and chronic kidney disease on renal function 1 1.1.2 Proliferation of cancer 3 1.1.3 Pre-tumour microenvironment 5 1.1.4 Pre-tumour inflammation 6 1.2 Von Hippel-Lindau Hereditary Syndrome 8 1.2.1 Introduction to VHL syndrome and ccRCC 8 1.2.2 ccRCC leading to spontaneous kidney failure 10 1.2.3 VHL ubiquitination on the pre-tumor environment 11 1.2.4 Markers of VHL syndrome 12 1.2.5 Role of cytokines in VHL/HIF dependent inflammation 13 1.2.6 Nervous system in VHL syndrome 1.3 GABA 17 1.3.1 Introduction and composition of GABA 17 1.3.2 Role of GABA in inhibiting tumorigenesis and immunity 18 1.3.3 GABA signalling in nerve formations 20 1.3.4 Leveraging GABA signalling in therapies 20 Chapter 2 Exploring the early impact of von Hippel-Lindau knock-out mice and the modulatory role of GABA in renal inflammation and nerve formation. 22 I. Introduction 22 II. Materials and methods 23 2.2.1 Animals 23 2.2.2 Experimental design 24 2.2.3 Behavioural examination 26 2.2.4 Tissue Preparation 28 2.2.5 Detection of serum, brain and urinary markers. 30 2.2.6 Immunohistochemistry 32 2.2.7 Determination of Cytokines 33 2.2.8 Statistical Analysis 35 III. Animal Model Results 37 2.3.1 Physiological disparities in Wild-Type and Vhlhfl/fl mouse 37 2.3.2 Effects of GABA treatment on serum and brain GABA levels and behaviour 39 2.3.3 Markers of inflammation and kidney damage in Vhlhdel/del mice 41 2.3.4 GABA treatment on nerve fibres of Vhlhfl/fl mice 44 2.3.5 Effects of GABA treatment on cytokines from mitogen-stimulated splenocytes 46 Chapter 3 The effects of GABA on nerve and cytokine in VHL knock-down cell cultures 50 I. Introduction 50 II. Materials and methods 51 3.2.1 Cell Lines 51 3.2.2 MTT 52 3.2.3 Transfection of RNA interference (RNAi) molecules 53 3.2.4 Cytokine analysis 56 3.2.5 Gene Expression 58 3.2.6 Western Blot 62 3.2.7 Immunostaining 67 III. Results 68 3.3.1 Transfection efficiency rate of VHL knock-down and cell viability 68 3.3.2 GABA treatment reduced proinflammatory cytokines in VHL knock-down cells 71 3.3.3 GABA induced inhibitory effect of VHL syndrome markers 72 3.3.4 GABA treatment inhibited NGF-induced neurite outgrowth of PC-12 cells 76 Chapter 4 Discussion and Conclusion 78 4.1 The role of VHL and GABA treatment on nerve growth 78 4.2 Behavioural impacts of VHL syndrome and GABA supplementation 80 4.3 Inflammation and immunomodulatory effect of GABA in VHL syndrome 82 4.4 GABA therapy on biomarkers of VHL syndrome 87 4.5 Variations in transfection efficiency of HEK293 and HK2 cells 88 4.6 Conclusion 91 Reference 93 Supplementary Material 104 | - |
| dc.language.iso | en | - |
| dc.subject | γ-胺基丁酸 | zh_TW |
| dc.subject | 細胞激素 | zh_TW |
| dc.subject | VHL | zh_TW |
| dc.subject | 神經生長 | zh_TW |
| dc.subject | 發炎 | zh_TW |
| dc.subject | inflammation | en |
| dc.subject | VHL | en |
| dc.subject | Gamma-aminobutyric acid | en |
| dc.subject | cytokines | en |
| dc.subject | nerve growth | en |
| dc.title | γ-胺基丁酸對von Hippel-Lindau缺失腎損傷模式的神經與免疫反應調控 | zh_TW |
| dc.title | Gamma-Aminobutyric Acid Modulates Neuronal and Immune Regulation in the von Hippel-Lindau Deficient Model of Renal Injury | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 江伯倫;江孟燦;徐沺;謝佳倩 | zh_TW |
| dc.contributor.oralexamcommittee | Bor-Luen Chiang;Meng-Tsan Chiang;Tien Hsu;Chia-Chien Hsieh | en |
| dc.subject.keyword | γ-胺基丁酸,發炎,神經生長,VHL,細胞激素, | zh_TW |
| dc.subject.keyword | Gamma-aminobutyric acid,inflammation,nerve growth,VHL,cytokines, | en |
| dc.relation.page | 106 | - |
| dc.identifier.doi | 10.6342/NTU202400126 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-01-23 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2029-01-18 | - |
| 顯示於系所單位： | 生化科技學系 | |
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