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研究生:邱敬絜
研究生(外文):CIOU, JING-JIE
論文名稱:剖析高鹽觸發自體免疫糖尿病的分子及細胞機制: 以基因改造小鼠模式為基礎的機轉分析及治療開發
論文名稱(外文):Dissection of molecular and cellular mechanisms involved in salt-triggered autoimmune diabetes: mechanistic and therapeutic studies by genetically modified mouse models
指導教授:司徒惠康司徒惠康引用關係
指導教授(外文):SYTWU, HUEY-KANG
口試委員:林石化許詔淵
口試委員(外文):LIN, SHIH-HUAHSU, CHAO-YUAN
口試日期:2021-05-13
學位類別:碩士
校院名稱:國防醫學院
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:英文
論文頁數:55
中文關鍵詞:第一型糖尿病高鹽
外文關鍵詞:Type 1 diabetesSPAKHigh salt diet
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自體免疫糖尿病又稱第一型糖尿病,肇因於自體免疫T細胞選擇性破壞胰臟內產生胰島素的β細胞。流行病學數據已指出第一型糖尿病的孩童可能從垃圾食物當中攝取過多的鹽量,造成有免疫疾病發生的傾向。為了瞭解高鹽對於第一型糖尿病疾病的影響,我們餵食非肥胖型糖尿病小鼠(NOD mice)高鹽飲食(包含含4%氯化鈉的飼料與含有1%氯化鈉的鹽水)。由我們的結果可以得知餵食小鼠高鹽飲食會加速小鼠糖尿病的疾病發展,並得知高鹽與自體免疫糖尿病的發展存在關聯性。另外,我們也發現高鹽所加劇的自體免疫疾病主要由CD4+ T細胞所主導。先前文獻指出富含Ste20-相關脯胺酸/胺基丙酸激酶(SPAK)能藉由磷酸化及活化鈉氯離子共同通道(NCC)來調控鈉離子的再吸收,且與腸道發炎有正向關聯。除此之外,最新文獻發現SPAK基因Stk39有個低頻率單核苷酸多型性(SNP)的變異對第一型糖尿病有極大的影響。由我們的結果當中,我們發現高鹽誘發NOD小鼠的CD4+ T 細胞Il21與Stk39的表現而導致疾病發展加劇。接著進一步剖析高鹽是否經SPAK調節NOD小鼠CD4+ T cell中的IL-21而導致免疫致病性,透過SPAK基因嵌入小鼠(Stk39F/F NOD mice) 與T細胞專一性Cre基因轉殖小鼠(LckCre transgenic NOD mice)交配,我們建立了T細胞專一性SPAK基因剔除小鼠(T-cell specific SPAK knockout mice)。結果顯示缺乏SPAK之CD4+ T細胞Il21表現下降,因而降低NOD小鼠胰島炎的嚴重程度及自發性糖尿病的症狀;我們亦發現T細胞專一性SPAK基因剔除糖尿病鼠能延緩高鹽所觸發之自體免疫糖尿病,因而推測高鹽所調控之SPAK在自體免疫糖尿病中扮演重要角色。另外,一種能夠抑制SPAK調控NCC磷酸化的抗寄生蟲藥物(Closantel)可減緩NOD小鼠的疾病發展,顯示SPAK可當作治療自體免疫疾病之標的。
Autoimmune diabetes, also known as type 1 diabetes (T1D), is caused by autoreactive T cells that selectively destroy the insulin-producing β cells in pancreatic islets. Epidemiological studies have reported that children with T1D overconsumed discretionary foods, which led to a high intake of sodium, potentially predisposing them to the immunopathogenic process of disease. To evaluate the potential effect of the high salt diet (HSD) on T1D, we fed non-obese diabetic (NOD) mice with sodium-rich chow containing 4% sodium chloride (NaCl) and tap water with 1% NaCl ad libitum. Our results indicated that HSD exacerbates the diabetic kinetics and severity of NOD mice in a CD4+ T cell-autonomous manner, compared to that in normal salt diet (NSD)-treated controls. Moreover, RNA-seq transcriptomic analysis on CD4+ T cells revealed that HSD enhances the Il21 and Stk39 expression. Recent studies have reported that interleukin-21 (IL-21) is essential for the development of autoimmune diabetes in NOD mice. Stk39 encodes a serine threonine kinase, Ste20-like proline/alanine-rich kinase (SPAK), which plays an important role in regulation of ion cotransporters. Moreover, the recent report indicated that Stk39 possesses a rare or low-frequency single nucleotide polymorphism (SNP) with large effects on risk of T1D. To further dissect whether IL-21-mediated immunopathogenicity in NOD mice is modulated by SPAK in a salt-regulated manner, we generated T cell-specific SPAK knockout mice by crossing Lck promoter driven Cre (LckCre) transgenic NOD mice with floxed Stk39 (Stk39F/F) NOD mice. Our results revealed that SPAK deficiency downregulates Il21 expression of CD4+ T cells, further reducing the severity of insulitis and attenuating spontaneous diabetes in NOD mice. Moreover, NOD mice with T cell-specific SPAK deletion were more resistant to HSD-triggered autoimmune diabetes, suggesting a pathogenic role of salt-modulated SPAK in the development of autoimmune diseases. Furthermore, Closantel, an anti-parasitic agent that inhibits SPAK-regulated phosphorylation and activation of NCC, ameliorates diabetogenesis in NOD mice, illustrating a SPAK-targeted immunotherapy for autoimmune diseases.
中文摘要 1
Abstract 2
Introduction 4
Chapter One: Introduction of Autoimmune diabetes 4
I Autoimmune Diabetes 4
II Non-Obese Diabetic Mice 5
III Etiology and Pathogenesis of Autoimmune Diabetes 6
Chapter Two: High Salt Diet 7
I Salt and Immunity 7
II The Role of Dietary Sodium in Autoimmune Diseases 9
Chapter Three: Ste20-related proline/alanine-rich kinase 9
I Ste20-Related Proline/Alanine-Rich Kinase (SPAK) 9
II SPAK and The Inflammatory Disease 10
III The Role of SPAK in T Cells 12
Specific aim 13
Materials and Methods 14
I Animals 14
II Diabetes Assessment 14
III Insulitis Assessment 14
IV T cell Isolation and Stimulation 15
V Adoptive Transfer 15
VI Flow Cytometry 16
VII Western Blot Analysis 16
VIII Quantitative RT-PCR 16
IX Statistical Analysis 17
Results 18
I The high salt diet triggers the development of autoimmune diabetes in NOD mice 18
II  The high salt diet exacerbates the diabetic kinetics and severity of NOD mice in a CD4+T cell-autonomous manner. 18
III NOD mice with T cell-specific deletion of SPAK are resistant to the development of autoimmune diabetes 20
IV Mice with T cell-specific deletion of SPAK attenaute the salt-triggered exacerbation of IL-21 mediated autoimmune diabetes 22
V Closantel, an anti-parasitic agent that inhibits SPAK-regulated phosphorylation and activation of NCC, ameliorates diabetogenesis in NOD mice 23
Conclusion 25
Discussion 26
Reference 29
Figures 36
Figure 1. The high salt diet exacerbates the development of diabetes in NOD mice. 36
Figure 2. Adoptive transfer of T1D by NSD- and HSD-received NOD splenocytes. 37
Figure 3. The high salt diet exacerbates the diabetic kinetics and severity of NOD mice in a CD4+ T cell-autonomous manner. 38
Figure 4. The high salt diet induced IL-21 expression of CD4+ T cells in NOD mice. 39
Figure 5. SPAK gene conventional deletion in NOD mice. 40
Figure 6. The generation of T cell-specific SPAK deletion NOD mice 41
Figure 7. SPAK deficiency in T cells attenuates the development of spontaneous diabetes and reduces the severity of insulitis in NOD mice. 42
Figure 8. NOD mice with T cell-specific SPAK deletion are more resistant to HSD-triggered autoimmune diabetes. 43
Figure 9. IL-21-mediated immunopathogenicity in NOD mice is modulated by SPAK in a salt-regulated manner. 44
Figure 10. The effect of SPAK deficency in CD4+ T cells in HSD-treated NOD mice. 45
Figure 11. The SPAK inhibitor closantel treatment ameliorates IL21-based diabetogenesis in NOD mice. 46
Figure 12. The effect on SPAK inhibitor closantel treatment in CD4+ T cells 47
Figure 13. The SPAK inhibitor—closantel attenuates the development of autoimmune diabetes in immunodeficient NOD recipient mice. 48
Figure 14. A proposed schematic of the pathophysiological role of SPAK in high salt diet-triggered autoimmune process in NOD mouse model. 49
Appendix 50
Table 1. Nutrition facts of rodent chow 50





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