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系統識別號 U0026-2308201015043700
論文名稱(中文) 探討過氧化體增生活化受體gamma與脂聯素系統在新生鼠腦部白質傷害中的角色
論文名稱(英文) Peroxisome Proliferator-Activated Receptor gamma -Adiponectin Axis in the White Matter Injury of Neonatal Brain
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) of Biochemistry and Molecular Biology
學年度 98
學期 2
出版年 99
研究生(中文) 陳竑達
研究生(英文) Hung-Ta Chen
電子信箱 vanofangel@gmail.com
學號 s1697409
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 指導教授-黃朝慶
召集委員-賴明德
口試委員-蔡曜聲
口試委員-張瑛玿
中文關鍵字 過氧化體增生活化受體-gamma  脂聯素  發炎  新生兒缺血缺氧性腦病變 
英文關鍵字 Peroxisome proliferator-activated receptor-gamma  Adiponectin  Inflammation  Neonatal Hypoxic ischemia brain injury 
學科別分類
中文摘要 新生兒缺血缺氧性腦病變係因大腦的血液與氧氣供應不足所引起,是造成新生兒死亡或長期神經病變的主要原因。在我們先前的研究中指出激活過氧化體增生活化受體-可以保護幼鼠因缺血缺氧所引起的腦部白質傷害。此外,過氧化體增生活化受體-基因缺失鼠(PpargP465L/+)則是會在缺血缺氧後表現更嚴重的腦部白質傷害。但是過氧化體增生活化受體-gamma保護新生幼鼠腦部缺血缺氧傷害的機制至今仍尚未明瞭。脂聯素,ADIPOQ,為過氧化體增生活化受體-的下游基因,已知與缺血性中風病人的癒後相關。我們推測過氧化體增生活化受體-gamma -脂聯素系統可保護由缺血缺氧所引起的新生幼鼠腦部傷害。
我們利用基因體及藥理學的方式觀察過氧化體增生活化受體-gamma與脂聯素兩者間的關係以及脂聯素對於缺血缺氧腦傷的保護效果。免疫化學呈色發現脂聯素主要表現於腦部血管中。我們發現給予新生幼鼠人類脂聯素的重組蛋白(3mg/Kg) 可促使腦部中脂聯素下游的AMPK與eNOS的磷酸化。脂聯素的治療可藉由降低小膠質細胞的活化來保護因缺血缺氧所引起的腦部白質傷害。在PpargP465L/+幼鼠體內,血液、腦部mRNA及腦部蛋白質中脂聯素的表現量均比正常幼鼠來得低。除此之外,利用免疫化學呈色也發現PpargP465L/+幼鼠大腦中脂聯素的表現較低且主要表現於血管。另一方面,我們給予出生後10天幼鼠rosiglitazone,過氧化體增生活化受體-gamma的活化劑,則發現與對照組相比之下,實驗組幼鼠體內脂聯素mRNA與蛋白質表現分別在6小時及24小時明顯提高。最後,我們同樣以人類脂聯素的重組蛋白治療PpargP465L/+幼鼠。我們發現脂聯素的治療可以減緩PpargP465L/+幼鼠因缺血缺氧而產生的腦部灰質與白質傷害以及降低小膠質細胞的活化。總結我們的實驗成果,我們發現過氧化體增生活化受體-gamma脂聯素系統在保護幼鼠缺血缺氧性腦病變中具有相當重要的角色。
英文摘要 Hypoxic ischemia (HI) is a major cause of neonatal mortality and long-term neurological morbidity among survivors. Our previous studies showed that activation of peroxisome proliferator-activated receptor-gamma (PPARgamma)significantly protected against HI injury in the white matter in postnatal day 10 (P10) mouse pups. In contrast, PPARG gene mutation (PPARgammaP465L/+) pups had significantly more white matter injury after HI than wild-type pups did. However, the PPARfamma-mediated protective mechanismagainstremains unknown. Adiponectin is an important PPARgamma downstream gene that shows anti-inflammation and vascular protection effect. In this study, we hypothesized that PPARgammaadiponectin axis is an important pathway in protecting against HI injury in neonatal brain.
Genetic and pharmacological approach was performed to determine the relationship between PPARgamma and adiponectin, and the protective effect of adiponectin against HI injury. Immunohistochemistry showed that adiponectin was expressed mainly in the cerebral blood vessels of P10 mouse pups. Treatment with adiponectin (3mg/kg, recombinant human adiponectin globular domain, intraperitoneal injection) phosphorylated adiponectin downstream signaling molecules, AMP-activate protein kinase (AMPK) and endothelial nitric oxide synthases (eNOS), in the cerebrum. Adiponectin treatment attenuated microglia activation and reduced white matter injury after HI in wild-type mouse pups. The plasma levels of adiponectin, and the mRNA and protein levels of adiponectin in the cerebrum were significantly lower in P10 PPARgammaP465L/+ pups than in wild-type mouse pups. The PPARgammaP465L/+ mouse pups also had lower levels of adiponectin in the cerebral blood vessels. Rosiglitazone, a PPAR agonist, treatment increased the plasma levels of adiponectin, and the mRNA and protein levels of adiponectin in P10 wild-type pups. PPARgammaP465L/+ pups treated with adiponectin showed attenuated microglia activation and protective effect in the hippocampus and white matter after HI. In conclusion, our study suggests that PPARgamma-adiponectin axis may play an important role in protecting against HI injury in the neonatal brain.
論文目次 Abstract 2
中文摘要 4
致謝 6
Contents 7
Figures 9
Introduction 11
Hypoxic ischemic injury in the neonatal brain 11
Neuroinflammation 12
Peroxisome proliferator-activated receptor  13
Adiponectin 15
PPAR-Adiponectin axis 19
Material and method 21
Animals 21
Hypoxic-ischemic brain injury in mouse pups 22
Genotyping: DNA preparation and PCR 22
Drug administration 23
Pathological assessment 24
Gray matter damage 24
White matter damage 25
Tissue RNA extraction 25
Reverse transcription and Real-Time PCR 26
Enzyme-Linked Immunosorbent Assay (ELISA) 27
Immunohistochemistry 27
Adiponectin expression 27
Microglia/macrophage activation 28
Western blot 29
Data analysis 30
Results 32
Injection of recombinant human globular adiponectin increased phosphorylation levels of AMPK and eNOS 32
Injection of recombinant human globular adiponectin protected against white matter injury after hypoxic ischemia in mouse pups 32
Adiponectin attenuated microglia activation in the hippocampus and white matter after hypoxic ischemia 33
Decreases of adiponectin levels in PPAR mutant pups 33
Rosiglitazone treatment increased adiponectin expression 34
Recombinant human globular adiponectin treatment reduced injury in the hippocampus and white matter after hypoxic ischemia in PpargP465L/+ mouse pups 35
Adiponectin treatment reduced microglia activation in the hippocampus and white matter after hypoxic ischemia in PpargP465L/+ mouse pups 36
Discussion 37
References 44
Appendix. 55
Biography note 67
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