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系統識別號 U0026-1501201210192300
論文名稱(中文) 體重對新生兒腦部經歷缺氧窒息腦傷害耐受性的影響
論文名稱(英文) The influence of body-weight on hypoxic-ischemic susceptibility in the neonatal brain
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 1
出版年 101
研究生(中文) 杜伊芳
研究生(英文) Yi-Fang Tu
學號 S9895112
學位類別 博士
語文別 英文
論文頁數 83頁
口試委員 指導教授-黃朝慶
指導教授-呂佩融
口試委員-蔡少正
口試委員-陳儀莊
口試委員-施能耀
口試委員-蔣思澈
口試委員-蔡曜聲
中文關鍵字 體重  節食  過重  新生兒缺氧窒息性腦傷害 
英文關鍵字 dietary restriction  overweight  neonatal hypoxic-ischemic encephalopathy 
學科別分類
中文摘要 周產期缺氧窒息腦病變是造成嬰兒死亡率及神經後遺症之一大原因,雖然目前對新生兒窒息腦傷機制的瞭解不少,但至今除了低體溫療法外仍無有效的治療。近年來有學者提出「Neurovascular unit」的概念。它是由神經元、星狀細胞、血管上皮細胞所組成的單元。缺氧窒息腦傷後,維持neurovascular unit的完整性,神經元才能繼續存活發揮功能。所以著手於尋找影響缺氧窒息腦傷害耐受性的因子,及其對neurovascular unit的影響,也是能預防甚至於治療缺氧窒息腦病變的方向。
臨床上的觀察發現,出生體重過重的新生兒易有產傷及遭遇周產期缺氧窒息的情形,而有神經後遺症。反之,體重不足的新生兒遭遇「周產期缺氧窒息」後卻較少有像腦性麻痺等嚴重的腦傷後遺症。這些臨床上的觀察顯示體重似乎會影響新生兒腦部對缺氧窒息腦傷害的耐受性。由一些關於肥胖的研究發現肥胖會促使脂肪細胞可分泌出許多促發炎細胞激素進而刺激活化c-Jun N-terminal kinase (JNK) 這個重要的kinase,JNK的活化也已知與細胞死亡機制相關,暗示體重過重的新生兒可能誘發JNK的過度激活惡化缺氧窒息性腦傷。另一方面的研究發現生物體在攝食量節制後,可以穩定細胞內的鈣離子,降低oxidative stress,減輕apoptosis,也可以影響p53的功能。p53 已知是個能調控細胞存亡的重要因子,所以攝食量節制可能可以藉由調控p53來幫助減輕缺氧窒息腦部的傷害。所以我們假設新生兒體重會影響新生兒腦部的「Neurovascular unit」 對缺氧窒息腦傷害的耐受性。
我們利用改變胎數的方法來建立過重及攝食量節制後減重的幼鼠模型。同天出生的幼鼠於出生第一天隨意分組: 正常組的母鼠一胎哺育12隻幼鼠,過重組的母鼠一胎只哺育6隻幼鼠,攝食量節制減重組的母鼠一胎則哺育18隻幼鼠。並於出生後第7天利用單側頸動脈結紮结合缺氧來誘發缺氧窒息腦傷害,藉由這些模型來測試體重對於新生兒期缺氧窒息腦傷害的影響。結果顯示,過重的幼鼠會誘發缺氧窒息後早期JNK的過度激活,引起細胞apoptosis且破壞neurovascular unit的完整性,造成球蛋白外漏、星狀細胞增加,加重缺氧窒息性腦傷。若抑制過重幼鼠的JNK表現,能改善過重的幼鼠在缺氧窒息腦傷後的傷害,減輕細胞apoptosis的程度及對 neurovascular unit的傷害。另一方面,減重的幼鼠在缺氧窒息後,減少p53的表現,降低了apoptosis、球蛋白外漏和星狀細胞,維持neurovascular unit的完整性,進而改善缺氧窒息性腦傷。進一步利用抑制Mdm2來增加p53在減重幼鼠的表現量,則發現減重的幼鼠會失去對缺氧窒息腦傷的保護效果,表示攝食量節制後減重的幼鼠能藉由調控p53來改善缺氧窒息性腦傷。
我們的結果發現單純的體重變化就能明顯影響新生兒腦部的「Neurovascular unit」 對周產期缺氧窒息腦傷害的耐受性,增加體重會藉由JNK的過度激活惡化缺氧窒息性腦傷,而攝食量節制後減重的幼鼠能藉由降低p53來改善缺氧窒息性腦傷。之後,我們會進一步探索攝食量節制後減重的幼鼠調控p53的機制,以期能運用在臨床周產期缺氧窒息腦傷害的治療上。
英文摘要 Perinatal hypoxic-ischemia (HI) is a major cause of neonatal mortality and of subsequent neurological disabilities among survivors. Neurovascular unit, comprised of neurons, astrocytes, microglia and endothelial cells, maintains the integrity of the blood-brain barrier and regulates the cerebral blood supply in response to the metabolic demand of the neurons. Modalities that target this integrated unit may yield more therapeutically useful results in treating perinatal HI.
From clinical observation in human newborns, large-for-gestational-age newborns who have above-average birthweights have higher incidences of birth complications, such as perinatal asphyxia, than appropriate-for-gestational-age (AGA) newborns. In contrast, small-for-gestational-age newborns with low birthweights have a lower incidence of cerebral palsy after perinatal insults than AGA newborns. These findings indicate that bodyweight may play an important role in the susceptibility of neonatal HI brain injury. Obesity studies showed that c-Jun N-terminal kinase (JNK) activated by obesity could precede cell death by apoptosis and inflammation in many cell types. Dietary restriction (DR) studies demonstrated that DR induced bodyweight reduction and protected neurons against focal ischemic brain damage. The gene profile in DR animals showed a decrease of p53, a transcription factor regulating cell cycle, DNA repair and cell apoptosis. Thus, we hypothesized that bodyweights have differential influence on the HI susceptibility in neonatal brain: overweight aggravated neurovascular damage and worsened HI injury through hyperactivation of JNK while DR-induced underweight reduced neurovascular damage and protected against HI injury via downregulation of p53.
We used changes of litter size to create overweight and underweight pup model. The overweight rat pups were induced by culling the litter size to 6 pups per dam from postnatal day 1 until weaning, and the control pups by keeping the litter size at 12. The underweight pups were raised in the litter size of 18 pups per dam. Our data showed that compared with normal bodyweight rat pups, overweight pups from a small litter size had increased susceptibility to HI injury on P7, evidenced by a high HI mortality, and worsened neurobehavioral performance and aggravated brain injury at long-term follow up. Overweight pups also had JNK hyperactivation soon after HI and increased neurovascular destruction, such as neuronal apoptosis, microglia activation and BBB damage, 24 hours after HI. Inhibiting JNK activity in overweight pups caused attenuation of cleaved caspase-3 and PARP, reduction of microglial activation and BBB damage and significantly reduced infarct brain volume after HI. On the other hand, compared with normal control pups, underweight pups induced by DR had decreased susceptibility to HI, supported by improved neurobehavioral performance and decreased brain injury at long-term follow up. Underweight pups also showed reduction of neuronal apoptosis, BBB damage and microglia activation and attenuation of p53 expression after HI. The neurovascular protection of underweight induced by DR was attenuated when p53 was activated by an Mdm2 inhibitor.
In conclusion, bodyweight has differential effects on the vulnerability of neonatal brain to HI injury involving the integrity of neurovascular unit. Overweight aggravated neurovascular damage through hyperactivation of JNK while DR-induced underweight protected against neurovascular damage via downregulation of p53.
論文目次 中文摘要 ---------------------------- 1
Abstract --------------------------- 4
Acknowledgement -------------------- 6
Contents ---------------------------- 8
Table content ---------------------- 9
Figure contents -------------------- 10
Abbreviation ----------------------- 11
Introduction ----------------------- 12
Material and Methods --------------- 16
Results ---------------------------- 24
Discussion ------------------------- 32
Table and Figure legends ----------- 44
Table ------------------------------ 51
Figures ---------------------------- 52
References ------------------------- 71
Thesis-related publications -------- 82
Publications during graduate program - 83
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