本實驗室早期透過昏迷病患之動脈壓頻譜偵測到源自於延腦鼻端網狀腹外側核之 “生與死” 的訊息，且其訊號消失於隨之而來的腦死之前。除此之外，於一系列之研究中進一步發現存在於延腦鼻端網狀腹外側核中之第二亞型一氧化氮合成酶於腦死過程中表現量增加是導致腦幹喪失調控心臟血管功能的主要原因。泛素–蛋白酶體系統已被證實不僅能調控參與第二亞型一氧化氮合成酶蛋白質新生成之路徑，亦能直接降解其蛋白質。因此，本論文進一步探討泛素–蛋白酶體系統於此模式下如何透過雙方面調節第二亞型一氧化氮合成酶蛋白質表現量與其於腦幹調控心臟血管功能之影響。我們採用Sprague-Dawley雄性大白鼠模擬臨床上腦幹死亡模式。前處理微量注射蛋白酶體活性抑制劑（lactacystin或proteasome inhibitor II）於雙側延腦鼻端網狀腹外側核中能阻斷因靜脈注射大腸桿菌酯多糖所誘發的低血壓與“生與死” 的訊號降低之現象，然而前處理泛素再循環抑制劑以及Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) 活性抑制劑卻造成更嚴重的低血壓以及“生與死”訊號之消失。此外，透過反轉錄聚合酶鏈式反應、西方墨點法、電泳移動遷移分析、染色質免疫沈澱分析以及共同免疫沈澱實驗等等之分子生物技術進一步發現蛋白酶體抑制劑能拮抗此模式下存在於細胞質中受磷酸化之I-κBα於第三期表現量降低、轉錄因子nuclear factor κB（NF-κB）於細胞核中之表現量以及其與第二亞型一氧化氮合成酶啟動子結合之表現量增加的現象。相較於前處理proteasome inhibitor II，利用decoy κB DNA抑制NF-κB啟動第二亞型一氧化氮合成酶基因的作用對於其蛋白質表現量抑制程度更多。前處理UCH-L1活性抑制劑會提高延腦鼻端網狀腹外側核中之第二亞型一氧化氮合成酶之蛋白質表現量與動物的死亡率，而其mRNA表現量於在此時期尚未顯著改變。根據本論文之研究結果，我們認為延腦鼻端網狀腹外側核中的泛素–蛋白酶體系統於實驗性內毒素敗血症腦幹死亡過程中透過活化NF-κB路徑開啟第二亞型一氧化氮合成酶之新生成以及對此合成酶直接進行降解作用之雙方面調節的機制，進一步參與腦幹於心臟血管之調控。我們的研究結果對於治療這類致命的病理現象提供了一些新穎的訊息。

Brain stem cardiovascular regulatory dysfunction during brain stem death is underpinned by an upregulation of nitric oxide synthase II (NOS II) in rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from blood pressure of comatose patients that disappears before brain stem death ensues. At the same time, the ubiquitin-proteasome system (UPS) is involved in the synthesis and degradation of NOS II. We assessed the hypothesis that the UPS participates in brain stem cardiovascular regulation during brain stem death by engaging in both synthesis and degradation of NOS II in RVLM. In a clinically relevant experimental model of brain stem death using Sprague-Dawley rats, pretreatment by microinjection into the bilateral RVLM of proteasome inhibitors (lactacystin or proteasome inhibitor II) antagonized the hypotension and reduction in the life-and-death signal elicited by intravenous administration of Escherichia coli lipopolysaccharide (LPS). On the other hand, pretreatment with an inhibitor of ubiquitin-recycling or UCH-L1 potentiated the elicited hypotension and blunted the prevalence of the life-and-death signal. Real-time polymerase chain reaction, Western blot, electrophoresis mobility shift assay, chromatin immunoprecipitation and co-immunoprecipitation experiments further showed that the proteasome inhibitors antagonized the augmented nuclear presence of NF-κB or binding between NF-κB and nos II promoter and blunted the reduced cytosolic presence of phosphorylated IκB. The already impeded NOS II protein expression by proteasome inhibitor II was further reduced after gene-knockdown of NF-κB in RVLM. In animals pretreated with UCH-L1 inhibitor and died before significant increase in nos II mRNA occurred, NOS II protein expression in RVLM was considerably elevated. We conclude that UPS participates in the defunct and maintained brain stem cardiovascular regulation during experimental brain stem death by engaging in both synthesis and degradation of NOS II at RVLM. Our results provide information on new therapeutic initiatives against this fatal eventuality.

中文摘要 i
英文摘要 iii
目 錄 v
圖 次 xii
表 次 xvi
第一章 緒論 1
1.1 腦幹死亡（Brain stem death） 1
1.1.1 腦幹死亡的定義 1
1.1.2 延腦鼻端網狀腹外側核（Rostral ventrolateral medulla, RVLM）於研究腦幹死亡模式中所扮演之角色 3
1.2 實驗性內毒素敗血症動物模式（Experimental endotoxemia animal model） 7
1.3 泛素-蛋白酶體系統（Ubiquitin-proteasome system, UPS） 8
1.3.1 UPS 之發現 8
1.3.2 UPS 之作用機轉 11
1.3.3 UPS 於臨床上敗血症或實驗性敗血症模式中之表現 16
1.3.4 UPS 與心臟血管功能之關係 17
1.4 一氧化氮（Nitric oxide, NO）於實驗性內毒素敗血症腦幹死亡動物模式中所扮演之角色 19
1.4.1 NO 之生合成反應 20
1.4.2 一氧化氮合成酶 20
1.4.3 NO 對於交感神經活性之調控與其進一步對心臟血管之影響 21
1.4.4 NOS-NO 於內毒素敗血症中所扮演的角色 24
1.4.5 UPS 於 NOS II 表現之調控 28
第二章 研究動機與目的 30
2.1 研究動機 30
2.2 研究目的 31
第三章 材料與方法 32
3.1 實驗動物與手術前處理 32
3.2 微量注射方式 32
3.2.1 微量注射至 RVLM 之定位方式 32
3.2.2 動物全身灌流與取樣 33
3.2.3 確認腦部微量注射位置 33
3.3 動脈壓頻譜分析 34
3.4 西方墨點法（Western blot） 35
3.4.1 蛋白質之萃取 35
3.4.2 蛋白質膠體電泳分離與免疫呈色反應 35
3.4.3 免疫沉澱分析（Immunoprecipitation, IP） 36
3.5 訊息核醣核酸（mRNA）表現量之測定 36
3.5.1 核醣核酸之萃取 36
3.5.2 反轉錄聚合酶鏈式反應 37
3.5.3 即時定量聚合酶鏈式反應（Real-time PCR） 37
3.6 染色質體免疫沈澱分析（Chromatin immunoprecipitation assay, ChIP assay） 38
3.7 電泳移動遷移分析（Electrophoretic mobility shift assay, EMSA） 39
3.7.1 細胞核蛋白質之萃取 39
3.7.2 細胞核內 NF-κB 與 DNA 結合之活性分析 40
3.8 Proteasome活性分析 41
3.9 蛋白質硝基化分析（Quantify protein nitration） 41
3.10 統計方法 42
第四章 實驗結果 43
4.1 大白鼠腦幹死亡之實驗性內毒素敗血症模式 43
4.1.1 靜脈注射 LPS 對於大白鼠血壓、心跳、動脈壓頻譜之血管運動成份功率密度以及存活率之影響 43
4.2 大白鼠 RVLM 中之 UPS 參與於實驗性內毒素敗血症腦幹死亡模式 44
4.2.1 大白鼠 RVLM 中 proteasome 於此模式下之表現情形 44
4.2.2 抑制 RVLM 中之 proteasome 活性於實驗性內毒素敗血症腦幹死亡模式下對於血壓、心跳、動脈壓頻譜之血管運動成份功率密度以及存活率之影響 44
4.2.3 抑制 RVLM 中之 proteasome 活性顯著增加蛋白質於實驗性內毒素敗血症腦幹死亡模式下泛素化之表現量 46
4.2.4 大白鼠 RVLM 中之 ubiquitin 於實驗性內毒素敗血症腦幹死亡模式下蛋白質與 mRNA 之表現情形 46
4.2.5抑制大白鼠 RVLM 中之 de-ubiquitination 能有效阻斷 ubiquitin 於實驗性內毒素敗血症腦幹死亡模式下蛋白質表現量增加之現象 47
4.2.6 大白鼠 RVLM 中之 UCH-L1 於實驗性內毒素敗血症腦幹死亡模式下之蛋白質與 mRNA 表現情形 47
4.2.7 抑制大白鼠 RVLM 中之 ubiquitin-recycling 作用於實驗性內毒素敗血症腦幹死亡模式下對於血壓、心跳、動脈壓頻譜之血管運動成份功率密度以及存活率之影響 48
4.3 大白鼠 RVLM 中之 UPS 在實驗性內毒素敗血症腦幹死亡模式下對於 NOS II 蛋白質表現之調控 50
4.3.1 大白鼠 RVLM 中 NOS II 之蛋白質與 mRNA 於實驗性內毒素敗血症腦幹死亡模式下兩者表現量之增幅具有極大的差異 50
4.3.2 抑制大白鼠 RVLM 中之 proteasome 活性顯著降低 NOS II 蛋白質與其 mRNA於實驗性內毒素敗血症腦幹死亡模式下所增加之表現量 51
4.3.3 抑制大白鼠 RVLM 中之 proteasome 活性顯著阻斷 NF-κB 路徑於實驗性內毒素敗血症腦幹死亡模式下之活化 52
4.3.4 利用 κB decoy DNA 干擾大白鼠 RVLM 中之 NF-κB 轉錄因子之活化於實驗性內毒素敗血症腦幹死亡模式下對於 NOS II 蛋白質表現量之影響 53
4.3.5 干擾大白鼠 RVLM 中之 ubiquitin-recycling 作用顯著增加 NOS II 於實驗性內毒素敗血症腦幹死亡模式下之蛋白質表現量 54
4.3.6 抑制大白鼠 RVLM 中之 UCH-1 活性於實驗性內毒素敗血症腦幹死亡模式下對 NOS II 之新生成與降解作用之影響 54
第五章 討論 56
5.1 大白鼠 RVLM 中之 UPS 參與於實驗性內毒素敗血症腦幹死亡模式 56
5.1.1 大白鼠 RVLM 中之 proteasome 活性於實驗性內毒素敗血症腦幹死亡模式下被誘導增加之現象造成心臟血管功能與 RVLM 神經活性之喪失 56
5.1.2 大白鼠 RVLM 中之 UCH-L1 於實驗性內毒素敗血症腦幹死亡模式初期維持 ubiquitin-recycling 之順暢且對於腦幹調控心臟血管功能產生保護作用 60
5.2 大白鼠 RVLM 中之 UPS 在實驗性內毒素敗血症腦幹死亡模式下對於 NOS II 蛋白質之表現進行雙方面調控 61
5.2.1 大白鼠 RVLM 中之 proteasome 於實驗性內毒素敗血症腦幹死亡模式中透過調節 NOS II 蛋白質表現量影響腦幹調控心臟血管功能之能力 62
5.2.2 存在於大白鼠 RVLM 中之 ubiquitin-recycling 於實驗性內毒素敗血症腦幹死亡模式下對 NOS II 之新生成與降解作用之影響 65
5.3 大白鼠 RVLM 中之 UPS 於實驗性內毒素敗血症過程中增加 NOS II 蛋白質表現量進而導致腦幹喪失調控心臟血管之功能 67
5.4 實驗設計之限制與藥物選擇之探討 68
5.4.1 實驗設計之限制 68
5.4.2 藥物選擇之探討 69
第六章 結論與展望 71
6.1 結論 71
6.2 未來展望 73
參考文獻 75
附圖、附表 130
附 錄 202

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