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系統識別號 U0026-1603201305035800
論文名稱(中文) 探討缺血前置處理保護幼鼠腦部對抗缺血缺氧腦傷的保護機制
論文名稱(英文) The protective mechanisms of ischemic preconditioning against hypoxic-ischemic brain injury in neonatal rats
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 林宛瑩
研究生(英文) Wan-Ying Lin
學號 S58941492
學位類別 博士
語文別 英文
論文頁數 112頁
口試委員 指導教授-黃朝慶
召集委員-沈孟儒
口試委員-林以行
口試委員-蔣輯武
口試委員-華瑜
口試委員-施能耀
中文關鍵字 缺血缺氧腦傷  缺血前置處理  幼鼠腦部  抗細胞凋亡 
英文關鍵字 hypoxic-ischemia  ischemic preconditioning  neonatal brain  cellular inhibitor of apoptosis 1 
學科別分類
中文摘要 新生兒「缺血缺氧腦傷」(hypoxia-ischemia, HI)是指新生兒在出生前後因缺血缺氧造成的腦部損傷,會引起癲癎、學習障礙、腦性麻痺等後遺症,嚴重甚至導致新生兒死亡。截至目前為止,針對HI形成的腦傷尚未有良好的預防或治療措施。「細胞凋亡」(apoptosis)是HI發生後造成細胞死亡重要的機制,並且apoptosis在發育中的腦部扮演著重要的角色。抗細胞凋亡途徑(anti-apoptotic pathway)主要會調控並抑制apoptosis的發生,其中Bcl-2及「抗細胞凋亡蛋白」(inhibitor of apoptosis proteins,IAP)為重要的抗細胞凋亡的分子。「缺血前置處理」(ischemic preconditioning, IP) 是指在致命性的缺血傷害發生之前,事先給予生物體一個短暫非致命性的缺血刺激,進而促使生物體產生對抗致命性傷害的保護機制。了解IP如何引起保護,未來我們可以利用此機制來達成預防及治療的效果。
過去多在成體的腦部中探討IP引起的保護機制,少有研究成功地在新生腦部建立IP模式。因此我們嘗試觀察短期(rapid)、中期(intermediate)及長期(delayed)的IP模式能否成功地被建立在新生鼠腦部。我們事先在新生鼠右側頸動脈以血管夾夾住2小時,分別在放開血管夾之後的2小時(2-h IP)、6小時(6-h IP)及22小時(22-h IP)再讓幼鼠接受HI。在HI發生後24小時,和未接受IP(no-IP)的組別比較,三個IP組別皆顯著地減少神經細胞的傷害並同時減少TUNEL-(+)的細胞。HI發生後35天到42天,經過行為測試及病理分析,我們證實了相較於no-IP組,三個IP組別皆呈現長期的腦部保護效果。no-IP組在HI發生後可以觀察到活化的caspase-3、poly (ADP-ribose) polymerase 和細胞核中的apoptosis inducing factor的表現量增加,三個IP組別則明顯地減少這些現象。在HI發生後,caspase-3和calpain會對細胞骨架蛋白α-spectrin 產生特異性蛋白水解片段,三個IP組別中只有delayed IP組可以顯著地降低此表現。此外,與控制組比較,no-IP組在HI後24小時會顯著地減少磷酸化CREB和粒線體Bcl-2的表現;反之,三個IP組別在HI發生後24小時,磷酸化CREB和粒線體Bcl-2的表現量呈現顯著增加。我們首先證實rapid IP、intermediate IP及delayed IP模式會活化CREB、增加Bcl-2的表現,進而阻止caspase-dependent 和caspase-independent apoptosis途徑,提供對抗HI的長期腦部保護現象。
我們進一步利用delayed IP探討IP引起腦部保護的機制。儘管過去針對腦部傷害的研究主要著重在神經細胞,近年來,許多研究指出神經和血管系統會互相聯繫並且透過相同的訊息傳遞作用在其目標,特別是在發育時期,神經和血管透過相互作用決定細胞的命運。由於IAP主要會調控並抑制apoptosis的發生,因此我們進一步探討是否在IP發生時,IAP會同時調控神經和血管系統進而促使幼鼠腦部產生對抗HI傷害的保護機制?
我們除了在in vivo的層級利用已經建立的delayed IP模式來研究對抗HI的保護機制,也於in vitro層級在SH-SY5Y神經細胞及HMEC-1血管內皮細胞成功地建立「氧糖去除」(oxygen-glucose deprivation, OGD) preconditioning模式,利用事先短暫地OGD處理產生對抗之後長期的OGD傷害。在in vivo的層級,我們發現IP會減少apoptosis的發生,並且在神經及血管內皮細胞中增加cellular IAP1 (cIAP1)的表現。利用small interfering RNA減少cIAP1在腦部的表現情形,會降低IP引起的腦部保護現象。在in vitro的層級,OGD preconditioning可以促進cIAP1表現並保護神經和血管內皮細胞對抗OGD的傷害。利用lentivirus-mediated short hairpin RNA降低cIAP1的表現,會減少OGD preconditioning對神經和血管內皮細胞形成的保護效果;相反地,利用lentiviral expression system增加cIAP1的表現,可以增加細胞對抗OGD傷害的能力。我們進一步證明了在IP發生時,cIAP1會透過共同調控神經和血管系統,進而促使幼鼠腦部產生對抗HI傷害的保護機制。
英文摘要 Hypoxia-ischemia (HI) is a major cause of neonatal mortality and neurologic disability in newborns. Apoptosis is a critical mechanism of cell death following HI in the immature brain. The anti-apoptotic brake can inhibit the apoptotic pathway to promote cell survival. Bcl-2 and cellular inhibitor of apoptosis 1 (cIAP1) are important endogenous anti-apoptotic brake. Ischemic preconditioning (IP) is a defense program in which exposure to sublethal ischemia followed by a period of reperfusion results in subsequent resistance to severe ischemic insults. Very few in vivo IP models have been established for neonatal brain. We examined whether rapid, intermediate, and delayed IP against HI could be induced in neonatal brain, and if so, whether the IP involved phosphorylation of cAMP response element-binding protein (pCREB) after HI. Postnatal day 7 rat pups were subjected to HI at 2 h (2-h IP), 6 h (6-h IP), or 22 h (22-h IP) after IP. We found all three IP groups had significantly reduced neuronal damage and TUNEL-(+) cells 24 hours post-HI than no-IP group. All three IP groups had long-term neuroprotection at behavioral and pathological levels compared with no-IP group. The increases of cleavage of caspase-3 and poly (ADP-ribose) polymerase and of cells with nuclear apoptosis inducing factor post-HI in no-IP group were all significantly reduced in three IP groups. The increases of caspase-3 and calpain-mediated proteolysis of α-spectrin post-HI were significantly reduced only in 22-h IP group. Furthermore, compared with control, the no-IP group had significant decreases of pCREB and mitochondria Bcl-2 levels in the ipsilateral cortex 24 hours post-HI. In contrast, the three IP groups had increased pCREB and mitochondria Bcl-2 levels, and significant differences were found between three IP and no-IP groups. In conclusion, IP, rapid, intermediate, or delayed, in neonatal rat brain activates CREB, up-regulates Bcl-2, induces extensive brakes on caspase-dependent and -independent apoptosis after HI, and provides long-term neuroprotection.
cIAP1 is an important regulator that inhibits apoptosis. Although neurons are the cellular target of IP, vessel tolerance also contributes greatly to protection. We hypothesized that cIAP1 is a shared molecule underlying IP-mediated neurovascular protection against HI in the neonatal brain. In vivo delayed IP was used and in vitro oxygen-glucose deprivation (OGD) preconditioning was established in SH-SY5Y neuronal cells and in HMEC-1 vascular endothelial cells. cIAP1 expression was inhibited by cIAP1 small interfering RNA (siRNA) in vivo or by lentivirus-mediated short hairpin RNA (LV-sh-RNA) in vitro, or was upregulated by the lentiviral expression system. IP reduced apoptosis, selectively increased cIAP1 in neurons and vascular endothelial cells, and provided long-term neuroprotection against HI. Intracerebroventricular delivery of cIAP1 siRNA significantly attenuated IP-mediated cIAP1 upregulation and neuroprotection in vivo. In vitro, OGD preconditioning induced cIAP1 and protected against OGD cell death in SH-SY5Y neuronal and HMEC-1 endothelial cells. Knockdown of cIAP1 by LV-sh-RNA decreased the protective effect of OGD preconditioning in SH-SY5Y and HMEC-1 endothelial cell, whereas overexpression of cIAP1 by lentivirus protected against OGD in these cells. In conclusion, cIAP1 is a shared molecule underlying IP-induced protection in neurons and vascular endothelial cells against HI in the neonatal brain.
論文目次 中文摘要......I
Abstract.......IV
誌謝......VII
Contents......IX
Figure List......XIV
Abbreviations......XVII
Introduction......1
Hypoxic-ischemia and the animal model......1
Pathogenesis of neonatal HI brain injury......2
Ischemic preconditioning......4
Anti-apoptotic brakes......6
The cAMP response element-binding protein......7
Neurovascular unit and neurovascular link......8
Aims......11
Materials and Methods.....13
Chemicals used......13
Animals used......16
Hypoxic-Ischemic brain injury......16
IP in Rat Pups......16
Morris water maze on P35......17
Tissue sectioning after HI......19
Pathological Outcome......19
Brain area reduction......19
Brain weight reduction......20
Histological measurement......20
TUNEL staining......20
Immunohistochemistry......21
Immunofluorescence staining......22
AIF-positive cell counting......22
NeuN-positive cell counting......23
Vessel Analysis......23
Western blot analysis......23
Immunoprecipitation assay......25
Real-Time polymerase chain reaction......25
Intracerebroventricular Delivery of cIAP1 Small
Interfering RNA......26
Cell culture......27
Oxygen-glucose deprivation......27
OGD cell death......28
OGD Preconditioning......28
Lactate Dehydrogenase measurement......29
Lentivirus-mediated silencing of cIAP1......30
Plasmid......30
Lentivirus-mediated overexpression......30
Statistics......31
Results......33
The effect of IP on neuropathology 24 hours after HI 33
Long-term neuroprotective effects of rapid, intermediate,
and delayed IP......34
Behavioral assessment from P35 to P40......34
Pathological measurement on P42......35
The effect of IP on apoptotic mechanisms after HI......35
Caspase-dependent pathway......35
Caspase-independent pathway......36
The effect of IP on pCREB and mitochondria Bcl-2
expression after HI......37
IP protected neurons and vascular endothelial cells
against hypoxic–ischemia......39
IP reduced apoptosis after HI......39
IP increased cIAP1 in neurons and endothelial cells after
HI......40
cIAP1 siRNA attenuated IP-induced cIAP1 and
neuroprotection......41
cIAP1 was required for preconditioning-mediated protection
against OGD in neurons and endothelial cells......42
cIAP1 over-expression in neurons and endothelial cells
protected against OGD......45
IP increased cIAP1 mRNA level and decreased cIAP1
ubiquitination......46
Discussion......48
Summary......64
Conclusion......65
References......66
Figures and Figure Legends......82
Publications......112
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