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研究生:王穎之
研究生(外文):Ying-Chih Wang
論文名稱:Luzp基因剔除/lacZ基因嵌入異型缺失合子成鼠的壓力反應探討
論文名稱(外文):Stress Response of Adult Luzp-Knouck-out/lacZ Knock-in Heterozygous Mice
指導教授:錢嘉韻錢嘉韻引用關係
指導教授(外文):Alice Chien Chang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:54
中文關鍵詞:海人酸癲癇神經退化
外文關鍵詞:kainic acidepilepsyneurodegenerationLUZP
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Luzp(Leucine zipper motif-containing protein 1)為張南驥教授實驗室所發現的基因,轉錄出之蛋白質含三個leucine-zipper motifs。以西方墨點法檢視LUZP在小鼠各組織的表現情形,發現LUZP主要表現於腦部,其分子量約為140 kDa。免疫組織染色法顯示,LUZP於成鼠腦部主要表現區域為大腦皮層(cerebral cortex)和海馬(hippocampus)等區域的神經細胞核中。張南驥教授實驗室後續亦建立了一小鼠種系,其中Luzp基因被剔除且以lacZ報導基因置換嵌入原Luzp基因之位置。由於Luzp同型缺失合子鼠(Homozygous Luzp-KO/lacZ-KI mice)會於出生前後死亡,故本實驗室利用異型缺失合子鼠(Heterozyous Luzp-KO/lacZ-KI mice)作為實驗動物模型,探討Luzp基因缺失之影響,推測Luzp在成鼠腦部之生理功能。鄭梅馨學姊發現給予25 mg/kg的kainic acid腹腔注射後,Luzp+/-小鼠較正常小鼠癲癇發作程度高且致死率明顯增加。顯示在藥物影響下,能夠誘導出異型缺失合子鼠的功能差異。
接續鄭梅馨學姊的研究,同時由於海馬迴在HPA axis中扮演關鍵性的負回饋角色可調控壓力反應,本論文亟欲探討LUZP是否具有調控壓力反應的功能。利用kainic acid主要作用目標在LUZP顯著表現的海馬迴,以單次腹腔注射20 mg/kg或21 mg/kg kainic acid即可誘導癲癇發作對小鼠造成急性壓力的特點,藉此建立一壓力模型來探討LUZP在成鼠中是否可能參與調控壓力反應。
首先降低劑量以20 mg/kg kainic acid注射Luzp+/-小鼠時,並未引起異型缺失合子更嚴重的癲癇發作,但當劑量提高至21 mg/kg時,初步結果顯示Luzp+/-小鼠對kainic acid的敏感度(susceptibility)會上升,顯示正常小鼠與Luzp+/-小鼠對kainic acid引起的癲癇反應具有閥值差異。後續以免疫組織染色法或神經退化性染色,分析相等癲癇發作級數之正常小鼠與Luzp+/-小鼠海馬迴中神經細胞受癲癇誘導引起之基因表達或細胞退化有無差異,初步結果發現:(1)只有以20 mg/kg kainic acid注射時,Luzp+/-小鼠在dentate gyrus背側及腹側區域,受癲癇誘導之1.5小時c-Fos表現量可能較正常小鼠有下降的趨勢,(2)注射21 mg/kg kainic acid三天後,正常小鼠CA3背側及腹側區域之glucocorticoid receptor(GR)表現稍微有下降的趨勢, Luzp+/-小鼠的GR表現則在CA1及DG的背側及腹側區域有下降的趨勢,(3)Luzp+/-小鼠注射20 mg/kg kainic acid三天後,海馬迴中dentate gyrus及hilus的腹側區域神經細胞退化現象可能較正常小鼠增加的趨勢,(4)注射20 mg/kg kainic acid三天後,正常小鼠與Luzp+/-小鼠在海馬迴的神經膠變性情形無明顯差異。
我懷疑當給予小鼠20 mg/kg KA引發三級到四級癲癇發作時, Luzp+/-小鼠的c-Fos在dentate gyrus受誘導程度較正常小鼠低,可能對於經kainic acid作用後dentate gyrus中神經細胞存活造成影響,推測可能由於一股Luzp基因缺失使c-Fos表現下降,造成神經保護作用降低,導致DG中有較正常小鼠更多的神經細胞死亡。然而在注射21 mg/kg KA時,癲癇發作六級的Luzp+/-小鼠中,c-Fos在DG的表現並未較癲癇發作四級的正常小鼠低。且限於目前並未得到癲癇發作六級的正常小鼠c-Fos表現,以及癲癇六級時兩種基因型小鼠的神經細胞死亡情形,故注射21 mg/kg KA之實驗結果,目前並無法支持上述推測。
Luzp, a novel gene with three leucine zipper motifs, were first identified from a murine bone marrow cDNA library. Western blot analysis indicated that LUZP is predominantly expressed in mice brain with an estimated molecular weight of about 140 kDa, whereas immunocytochemistry data clearly revealed its presence in the nucleus of principle neuron of cerebral cortex, and hippocampus, etc. Professor NCChang’s lab has established a Luzp-KO/lacZ-KI mutant mice model, of which the homozygous Luzp-KO/lacZ-KI mutant mice are embryonic lethal. Thus, we use the heterozygous mutant containing one allele of Luzp as our model, to unravel the physiological function of LUZP in adult CNS via the pharmocogenetic approach. MHC has found that, giving peritoneal injection of 25mg/kg of kainic acid to the heterozygous Luzp-KO/lacZ-KI mice can induce a higher degree of seizure and higher mortality after extensive convulsive seizures than control groups.

According to MHC’s finding on the heterozygous Luzp-KO/lacZ-KI mice and the role of hippocampus which modulates negative feedback inhibition to the HPA axis responsive to stress, we want to investigate whether the recessive gene, Luzp regulates stress response in adult mice in this study, by establishing a stress paradigm, of which the single peritoneal injection at the does of 20mg/kg or 21mg/kg, targeting highly-expressed LUZP hippocampus, is able to induce mice hippocampus seizure and elicit acute stress for mice.

Giving injection of lower dose at 20 mg/kg, the heterozygous Luzp-KO/lacZ-KI mice didn’t show a higher degree of seizure, but injection of dose at 21 mg/kg showed a preliminary result that the susceptibility to kainic acid of Luzp-KO/lacZ-KI mice increased. This revealed the difference of threshold between wild type and Luzp-KO/lacZ-KI mice. Immunocytochemistry or silverstain of neurodegeneration was subsequently used to analyze both the wild type and Luzp-KO/lacZ-KI mice with the same degree of seizure, to study if there is any difference in the seizure-induced gene expression of neuron and neurodegeneration. The results demonstrated that (1) only when kainic acid injection of 20 mg/kg is given, c-Fos expression at dorsal and ventral parts of dentate gyrus in Luzp-KO/lacZ-KI mice tends to be lower after being injected for 1.5 hours, (2) three days after the kainic acid injection of 21 mg/kg, glucocorticoid receptor expression at the dorsal part and ventral part of CA3 in the wild type mice, tends to decrease slightly, while glucocorticoid receptor expression at the dorsal part and ventral part of both CA1 and DG in the Luzp-KO/lacZ-KI mice, tends to decrease, (3) three days after the kainic acid injection of 20 mg/kg, neurodegeneration in ventral part of dentate gyrus and hilus tends to increase, (4) three days after the kainic acid injection of 20 mg/kg, gliosis in hippocampus shows no difference between wild type and Luzp-KO/lacZ-KI mice.

From the observations above, it is assumed that in the cases of seizure scored 3 and seizure scored 4 induced by kainic acid injection of 20 mg/kg, lower expression of c-Fos at dentate gyrus after seizure, in Luzp-KO/lacZ-KI mice may affect neuron survival of dentate gyrus damaged by kainic acid. We also hypothesized that the lower expression of c-Fos may due to the lost of one allele of Luzp, decrease the neuroprotection, which subsequently causes more neurons of dentate gyrus in Luzp-KO/lacZ-KI mice to die than wild type mice. However, after the kainic acid injection of 21 mg/kg, the c-Fos expression at DG in wild type with seizure scored 4 and in Luzp-KO/lacZ-KI mice with seizure scored 6, show no difference. Besides, the data of c-Fos expression of wild type mice with seizure scored 6 could not be obtained by now, and neurodegeneration also occurred in both wild type and Luzp-KO/lacZ-KI mice with seizure scored 6. Therefore, the experimental data of kainic acid injection of 21 mg/kg does not support the assumption according to the data of kainic acid injection of 20mg/kg.
中文摘要------------------------------------------------I
英文摘要----------------------------------------------III
壹、 緒論--------------------------------------------1
一、LUZP背景介紹
二、海馬迴結構
三、壓力與HPA axis
四、癲癇與顳葉癲癇
五、致癲癇藥物海人酸(kainite or kainic acid;KA)
六、海人酸誘導癲癇發作與誘導immediate early gene表現
七、海人酸誘導癲癇發作與神經細胞退化
八、海人酸誘導癲癇發作與神經膠變性
九、研究目標
貳、 材料與方法------------------------------------------13
一、Luzp基因剔除小鼠(knockout mice)來源與基因型鑑定
二、腹腔注射致癲癇藥物海人酸誘發小鼠癲癇發作
三、組織灌流
四、腦組織切片與原位X-gal染色法(in situ X-gal staining)
五、免疫組織染色法
六、神經退化銀染
七、免疫組織染色強度定量分析
八、統計分析
參、 驗結果與分析------------------ -------------------22
一、以20 mg/kg KA誘導小鼠癲癇發作
二、以21 mg/kg KA 誘導小鼠癲癇發作
三、小鼠癲癇發作誘導c-Fos表現
四、小鼠癲癇發作對壓力賀爾蒙受器GR表現量之影響
五、KA誘導小鼠癲癇發作引起神經細胞退化
六、注射KA誘導癲癇發作,引發神經膠細胞活化
肆、 綜合討論與未來展望----------------------------------37
伍、 參考文獻--------------------------------------------47
陸、 圖表------------------------------------------------55
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