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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林君榮(Chun-Jung Lin) | |
dc.contributor.author | Yu-Han Kao | en |
dc.contributor.author | 高于涵 | zh_TW |
dc.date.accessioned | 2021-06-08T01:38:28Z | - |
dc.date.copyright | 2017-02-24 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-09-08 | |
dc.identifier.citation | Abbott, N.J., L. Ronnback, and E. Hansson. 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 7:41-53.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18884 | - |
dc.description.abstract | 第一部分:P-glycoprotein在漢丁頓舞蹈症中的表現及功能與其對於精神病用藥影響之探討
漢丁頓舞蹈症為一神經退化疾病,主要原因為變異漢丁頓蛋白質帶有過度擴張的穀胺醯胺胺基酸 (polyglutamine; polyQ),其變異會造成許多受影響的基因轉錄失衡。P-glycoprotein (P-gp) 是血腦障壁單元中微血管內皮細胞膜上重要的向外幫浦轉運蛋白,此研究目的為探討P-gp在漢丁頓舞蹈症之調控與功能表現。實驗結果顯示轉殖人類變異基因的疾病小鼠模式R6/2,相較於控制組小鼠其腦部微血管有明顯偏高的P-gp mRNA以及蛋白質表現,同時伴隨著NF-κB活性增加。在漢丁頓舞蹈症患者腦部組織也觀察到較高的P-gp蛋白質表現。利用微透析技術測量P-gp受質精神病用藥risperidone和其活性代謝物paliperidone的腦部細胞外液濃度,以及利用萃取腦部及血液濃度計算藥物腦血比(brain-to-blood ratio),結果顯示與較高的P-gp表現量現象一致,其細胞外藥物濃度和腦血比在R6/2模式小鼠都顯著降低,顯示P-gp的功能也同時上升。體外試驗將細胞株HEK293T轉染人類變異huntingtin基因(mHTT-109Q)相較於轉染正常基因(HTT-25Q)的細胞株,P-gp mRNA表現量以及NF-κB活性皆有顯著增加,若同時給予IKK抑制劑BMS-345541抑制NF-κB活性,則會反轉P-gp mRNA表現量增加之現象。這些結果顯示,變異的漢丁頓蛋白質會經由NF-κB路徑使得漢丁頓舞蹈症的腦部微血管P-gp表現量及功能異常增加,且大大的將低其藥物在腦中的濃度。 第二部分:ENT1在漢丁頓舞蹈症小鼠腦內表現量以及其對於腺苷(Adenosine)濃度影響之評估 漢丁頓舞蹈症是遺傳性神經退化疾病,目前臨床上除了症狀緩解處理並無可治癒的藥物。漢丁頓舞蹈症會造成特定腦區紋狀體明顯萎縮,此部分神經元高度表現的腺苷 (adenosine) A2A受體 (A2AR),腺苷經與細胞表面受體作用,在調控神經系統傳遞及突觸功能上扮演重要的角色,因此腺苷系統的衡定受到擾動與神經退化疾病有高度相關。此部分研究目的為探討核苷轉運蛋白ENT1的表現與功能是否因HD病理狀態而改變,及其對於細胞外腺苷濃度之影響。首先,實驗結果顯示腺苷及腺嘌呤核苷酸的腦中濃度在漢丁頓舞蹈症基因轉殖鼠(R6/2模式)以及病患中被不正常的調控。在人類,腺苷除以三磷酸腺苷(ATP)濃度的比例、三磷酸腺苷濃度分別與發病長短和CAG三個核苷酸重複序列長度呈現高度負相關。在動物,與野生型(wild-type)相比較,漢丁頓舞蹈症疾病小鼠的核苷轉運蛋白ENT1表現量上升。除此之外,從腦部灌流ENT1抑制劑(NBTI與dipyridamole)會造成在疾病小鼠腦部細胞外液較高幅度的核苷濃度的增加,顯示漢丁頓舞蹈症中ENT1轉運核苷的功能增加。值得注意的是,dipyridamole與NBTI併用對腺苷濃度所造成的影響比單獨投予NBTI持續較長。另一方面,由微透析證明腹腔給予腺苷類似物JMF1907可通過血腦障壁進入腦內,也可增加紋狀體區域的腺苷細胞外含量。總合以上,我們的結果顯示漢丁頓舞蹈症的以腺苷為基礎的系統失衡,並且其核苷轉運蛋白ENT1的表現量和功能皆較野生型小鼠上升,未來需要進一步的研究探討是否可經由抑制ENT1做為治療漢丁頓舞蹈症之標的。 | zh_TW |
dc.description.abstract | Part I: Regulation of P-glycoprotein expression in brain capillaries in Huntington’s disease and its impact on brain availability of antipsychotic agents
Huntington’s disease (HD) is a neurodegenerative disease marked by an expanded polyglutamine (polyQ) tract on the huntingtin (HTT) protein that may cause transcriptional dysfunction. This study aimed to investigate the regulation and function of P-glycoprotein, an important efflux transporter, in brain capillaries in HD. The results showed that, compared with the littermate controls, R6/2 HD transgenic mice with the human mutant HTT gene had higher levels of P-glycoprotein mRNA and protein and enhanced NF-κB activity in their brain capillaries. Higher P-glycoprotein expression was also observed in the brain capillaries of human HD patients. Consistent with this enhanced P-glycoprotein expression, brain extracellular levels and brain-to-plasma ratios of the antipsychotic agents risperidone and paliperidone were significantly lower in R6/2 mice than in their littermate controls. Exogenous expression of human mutant HTT protein with expanded polyQ (mHTT-109Q) in HEK293T cells enhanced the levels of P-glycoprotein transcripts and NF-κB activity compared with cells expressing normal HTT-25Q. Treatment with the IKK inhibitor, BMS-345541, decreased P-glycoprotein mRNA level in cells transfected with mHTT-109Q or normal HTT-25Q. In conclusion, mutant HTT altered the expression of P-glycoprotein through the NF-κB pathway in brain capillaries in HD and markedly affected the availability of P-glycoprotein substrates in the brain. Part II: Investigation of the expression levels of equilibrate nucleoside transporter 1 (ENT1) and its impacts on adenosine levels in Huntington’s disease Huntington's disease (HD) is a dominantly inherited neurodegenerative disease whose treatment is only available for symptomatic relief. The pathological hallmark of HD is the selectively considerable loss of neurons in striatum, which highly express adenosine A2A receptors. By acting on adenosine receptors, adenosine fine tunes neurotransmitters and synaptic plasticity. Thus, the imbalance of adenosine homeostasis may exacerbate to the HD neuropathology. The present study aimed to investigate the regulation of equilibrative nucleoside transporter-1, ENT1, to HD pathology and its impacts on brain extracellular levels of adenosine. First, our results showed that adenosine homeostasis was dysregulated in the brains of R6/2 transgenic HD mice and of patients with HD. The adenosine:ATP ratio and the ATP level in the cerevral spinal fluid of HD patients were inversely correlated with the number of CAG repeats and disease duration, respectively. In comparison to wild-type mice, expression of ENT1 was higher in the striatum of R6/2 mice. Intrastriatal administration of ENT1 inhibitors, NBTI and dipyridamole, caused a higher increase in extracellular levels of adenosine in the striatum of HD mice than in WT mice, suggesting that the function of ENT1 in the striatum was higher in HD mice than in WT mice. Nevertheless, it is noted that the increase of extracellular adenosine levels sustained longer when dipyridamole was coadministrated with NBTI, compared to the administration of NBTI alone. An intraperitoneal administration of JMF1907, an adenosine analogue, can also increase extracellular adenosine levels. Collectively, our results showed the adenosine homeostasis is abnormally regulated in mice and humans with HD. The expression of ENT1 was up-regulated, whose inhibition can enhance extracellular adenosine level in HD. Further studies are required to verify whether the inhibition of ENT1 can be pharmacologically beneficial to the treatment of HD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T01:38:28Z (GMT). No. of bitstreams: 1 ntu-105-D00423101-1.pdf: 4518776 bytes, checksum: 9d5d0e76dc557f7cd2dd1bfe928232ec (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | ABSTRACT I
PART I: REGULATION OF P-GLYCOPROTEIN EXPRESSION IN BRAIN CAPILLARIES IN HUNTINGTON’S DISEASE AND ITS IMPACT ON BRAIN AVAILABILITY OF ANTIPSYCHOTIC AGENTS I PART II: INVESTIGATION OF THE EXPRESSION LEVELS OF EQUILIBRATE NUCLEOSIDE TRANSPORTER 1 (ENT1) AND ITS IMPACTS ON ADENOSINE LEVELS IN HUNTINGTON’S DISEASE III 中文摘要 V 第一部分:P-GLYCOPROTEIN在漢丁頓舞蹈症中的表現及功能與其對於精神病用藥影響之探討 V 第二部分:ENT1在漢丁頓舞蹈症小鼠腦內表現量以及其對於腺苷(ADENOSINE)濃度影響之評估 VI 第一章 緒論 1 1.1 漢丁頓舞蹈症 1 1.2 漢丁頓舞蹈症之治療現況 2 1.3 漢丁頓舞蹈症的生物標記 4 第二章 研究目的 8 第三章 P-GLYCOPROTEIN在漢丁頓舞蹈症中的表現及功能與其對於精神病用藥影響之探討 9 3.1 文獻回顧 9 3.1.1血腦障壁 9 3.1.2 P-glycoprotein (P-gp) 9 3.1.3 P-gp與腦部相關疾病 10 3.1.4 NF-κB與漢丁頓舞蹈症 11 3.2 實驗材料與方法 13 3.2.1 實驗材料 13 3.2.1.1 試劑 13 3.2.1.2 溶液配方 14 3.2.1.3 材料與設備 15 3.2.2 實驗動物 16 3.2.3 組織RNA萃取及cDNA製備及即時定量聚合酶連鎖反應 17 3.2.3.1 組織萃取RNA 17 3.2.3.2 反轉錄製備互補DNA 18 3.2.3.3 即時定量聚合酶連鎖反應(RT-QPCR) 18 3.2.4 麻醉小鼠腦部微透析實驗 19 3.2.4.1 體外回收率測試 19 3.2.4.2 腦部定位 19 3.2.4.3 腦部微透析 19 3.2.5 血中濃度及腦部含量分析 20 3.2.5.1 藥品製備 20 3.2.5.1 給藥及小鼠血樣採集 20 3.2.5.2 血樣萃取方法 20 3.2.5.3 腦部組織萃取方法 20 3.2.6 藥物定量分析 21 3.2.6.1 體外回收率定量分析 21 3.2.6.2 藥物體內含量檢測分析 21 3.2.7 免疫組織化學染色 21 3.2.7.1 小鼠腦部冷凍切片 21 3.2.7.2 小鼠免疫組織化學染色 22 3.2.7.3 人腦組織檢體來源及切片 22 3.2.7.4 人腦免疫組織化學染色 23 3.2.8 分離腦部微血管及腦部細胞膜層 23 3.2.8.1 分離小鼠腦部微血管及萃取蛋白質 23 3.2.8.2 小鼠腦部細胞細胞膜蛋白萃取 24 3.2.9 西方墨點法 (western blotting) 24 3.2.9.1 蛋白質濃度測定 24 3.2.9.2 西方墨點法 25 3.2.10 體外細胞試驗 25 3.2.10.1 細胞株培養 25 3.2.10.2 質體轉染 (TRANSFECTION) 26 3.2.11 數據分析 26 3.2.11.1 藥物動力學分析 26 3.2.11.2 統計分析 27 3.3 實驗結果 30 3.3.1 R6/2 HD小鼠腦部微血管中NF-κB之活性 30 3.3.2 R6/2 HD小鼠組織中P-gp、Mrp2以及Bcrp mRNA之表現 30 3.3.3 漢丁頓舞蹈症病患及基因轉殖鼠腦部P-gp蛋白質表現 31 3.3.4 變異的HTT蛋白質對於P-gp表現量之影響 31 3.3.5 HD小鼠腦部細胞外risperidone及paliperidone之濃度 32 3.3.6 HD小鼠血漿中risperidone及paliperidone之濃度 33 3.4 結果討論 46 3.5 結論 49 第四章 ENT1在漢丁頓舞蹈症小鼠腦內表現量以及其對於腺苷(ADENOSINE)濃度影響之評估 50 4.1 文獻回顧 50 4.1.1 腺苷與漢丁頓舞蹈症 50 4.1.2 腦內腺苷調控 51 4.1.3 核苷轉運蛋白 51 4.2 實驗材料與方法 55 4.2.1 實驗材料 55 4.2.1.1 試劑 55 4.2.1.2 材料與設備 55 4.2.1.3 腦脊髓液檢品 56 4.2.2 實驗動物 56 4.2.3組織RNA萃取及cDNA製備及即時定量聚合酶連鎖反應 56 4.2.3.1 組織萃取RNA 56 4.2.3.2 反轉錄製備CDNA 57 4.2.3.3 即時定量聚合酶連鎖反應 57 4.2.4 清醒小鼠腦部微透析實驗 58 4.2.4.1 體外回收率測試 58 4.2.4.2 腦部定位並埋入探針外管 58 4.2.4.3 清醒小鼠腦部微透析 58 4.2.5 腦組織萃取腺嘌呤核苷及核苷酸 59 4.2.5.1 取腦步驟 59 4.2.5.2 萃取方法 59 4.2.6 腺嘌呤核苷及核苷酸螢光衍生化及極致液相層析 60 4.2.6.1 螢光衍生化 60 4.2.6.2 高效能液相層析 60 4.2.7 極致液相層析 61 4.2.7.1 體外回收率樣品分析 61 4.2.7.2 微透析樣品JMF1907含量分析 61 4.2.8 數據分析 61 4.3 實驗結果 64 4.3.1 漢丁頓舞蹈症病患腦內腺苷系統失調 64 4.3.2 漢丁頓舞蹈症轉殖基因鼠R6/2腦內腺苷系統失調 64 4.3.3 漢丁頓舞蹈症影響腺苷轉運蛋白的表現 65 4.3.4 漢丁頓舞蹈症影響腺苷轉運蛋白的功能 65 4.3.5 給予JMF1907對於細胞外腺苷濃度之影響 66 4.4 結果討論 75 4.5 結論 79 第五章 結論 80 第六章 參考文獻 81 | |
dc.language.iso | zh-TW | |
dc.title | 轉運蛋白在治療漢丁頓舞蹈症上扮演的角色
第一部分:P-glycoprotein在漢丁頓舞蹈症中的表現及功能與其對於 精神病用藥影響之探討 第二部分:ENT1在漢丁頓舞蹈症小鼠腦內表現量以及其對於腺苷 (Adenosine)濃度影響之評估 | zh_TW |
dc.title | Roles of transporters on the treatment of Huntington’s disease
Part I: Regulation of P-glycoprotein expression in brain capillaries in Huntington’s disease and its impact on brain availability of antipsychotic agents Part II: Investigation of the expression levels of equilibrate nucleoside transporter 1 (ENT1) and its impacts on adenosine levels in Huntington’s disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林榮信(Jung-Hsin Lin),劉宏輝(Horng-Huei Liou),陳儀莊(Yijuang Chern),陳瓊美(Chiung-Mei Chen) | |
dc.subject.keyword | 漢丁頓舞蹈症,血腦障蔽,P-glycoprotein,腺?,腺?轉運蛋白, | zh_TW |
dc.subject.keyword | Huntington’s disease,blood-brain barrier,P-glycoprotein,risperidone,paliperidone,adenosine,ENT1, | en |
dc.relation.page | 89 | |
dc.identifier.doi | 10.6342/NTU201603582 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2016-09-08 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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