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題名 BK離子通道與海馬迴粒細胞死亡的相關性
The relationship between BK channel alternative splicing and granule cell death in the hippocampus
作者 吳君逸
Wu, Jun Yi
貢獻者 賴桂珍
Lai, Guey Jen
吳君逸
Wu, Jun Yi
關鍵詞 BK離子通道
海馬迴
齒狀回
BK
Hippocampus
Dentate gyrus
日期 2011
上傳時間 30-十月-2012 15:22:10 (UTC+8)
摘要 海馬迴不僅在學習與記憶中扮演重要的角色，在許多神經退化性疾病中亦佔有重要的地位。海馬迴的齒迴內側區是哺乳動物大腦中成體幹細胞主要來源區域之一，其所新生的海馬迴粒細胞會往上遷移至海馬迴粒細胞層並與固有神經細胞形成功能性連結。
     過去的研究發現太少或過量的壓力荷爾蒙均會造成海馬迴粒細胞的死亡，而一定量濃度的皮質固醇對於維持海馬迴粒細胞的生存亦扮演非常重要的角色。在摘除兩側的腎上腺後，海馬迴粒細胞在幾週後會逐漸死亡且造成認知功能的缺損。本實驗即利用雙側腎上腺摘除術建立動物模式，企圖了解海馬迴粒細胞在凋亡的過程中所產生的生理層面的改變。
      壓力荷爾蒙（包含皮質固醇，在老鼠稱為corticosterone，在人類稱為cortisol）為腎上腺皮質分泌激素，已知會參與並調控BK 離子通道的選擇性剪接。BK離子通道的孔道形成α次單元由單一基因 (Slo) 負責轉錄，含有STREX外顯子的剪接變異體之α次單元藉由加速神經細胞的再極化，增強過極化電位以及促進鈉離子通道自去活化狀態中回復可造成神經細胞重複激發，而先前的研究已發現過度的激發會對神經細胞產生興奮性毒殺作用。本實驗即探討BK 鉀離子通道選擇性剪接在海馬迴粒細胞凋亡的過程中所扮演的角色。 實驗結果發現，與對照組相比，雙側腎上腺摘除的老鼠海馬迴細胞中含有STREX外顯子的剪接變異體在mRNA含量上確實有改變，而BK 鉀離子通道蛋白質含量亦有所變化。由上述結果推測，含有STREX外顯子的剪接變異體含量可能與海馬迴粒細胞的凋亡機制有關。
The hippocampus is a brain region central to learning and memory and is a key target of many neurological diseases that have dramatic cognitive consequences, including Alzheimer’s and other forms of dementia, stroke, epilepsy, and chronic stress. Hippocampal granule cells are one of the two cell pools that contain newborn neurons continuously generated from the subgranular zone in adult mammalian brains. The newborn neurons will migrate to the granule cell layer and integrate into preexisting neuron network. Previous studies have indicated that both an excessive and insufficient levels of stress hormones can lead to neuron death. Corticosterone, an adrenal stress hormone, is essential for the survival of granule cells. Bilateral removal of adrenal glands leads to extensive granule cell death over a period of several weeks and gradually causes cognitive deficits. To understand the mechanisms underlying the granule cell death in the hippocampal formation, adrenalectomy (ADX, removal of adrenal glands) was used to specifically eliminate granule cells in the hippocampus, and the subsequent physiological changes in the hippocampal neurons including dentate granule cells are investigated.
     
     Stress hormones (corticosterone in rats and cortisol in human) , secreted from the adrenal cortex regulate the alternative splicing of BK channels (big potassium, calcium-voltage activated potassium channels) in adrenal medulla. An inclusion of STREX (stress axis-regulated exon) exon in pore-forming α subunit encoded by Slo gene promotes repetitive firing by speeding action potential repolarization and augmenting the afterhyperpolarization, as well as facilitating sodium channels de-inactivation. In the present study, the role of BK channel alternative splicing in the ADX-induced granule cell death in the hippocampus was explored. The results indicate that BK channel alternative splicing was regulated by stress hormones in the hippocampus including dentate gyrus. The expression patterns of STREX variant in hippocampus were altered after granule cells death induced by ADX, whilst the expression of total slo gene was changes only in translational level. These observations suggest that the alternation in STREX abundance might be involved in the induction of dentate granule cell death.
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描述 碩士
國立政治大學
神經科學研究所
97754001
100
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0097754001
資料類型 thesis
dc.contributor.advisor 賴桂珍zh_TW
dc.contributor.advisor Lai, Guey Jenen_US
dc.contributor.author (作者) 吳君逸zh_TW
dc.contributor.author (作者) Wu, Jun Yien_US
dc.creator (作者) 吳君逸zh_TW
dc.creator (作者) Wu, Jun Yien_US
dc.date (日期) 2011en_US
dc.date.accessioned 30-十月-2012 15:22:10 (UTC+8)-
dc.date.available 30-十月-2012 15:22:10 (UTC+8)-
dc.date.issued (上傳時間) 30-十月-2012 15:22:10 (UTC+8)-
dc.identifier (其他 識別碼) G0097754001en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/55036-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 97754001zh_TW
dc.description (描述) 100zh_TW
dc.description.abstract (摘要) 海馬迴不僅在學習與記憶中扮演重要的角色，在許多神經退化性疾病中亦佔有重要的地位。海馬迴的齒迴內側區是哺乳動物大腦中成體幹細胞主要來源區域之一，其所新生的海馬迴粒細胞會往上遷移至海馬迴粒細胞層並與固有神經細胞形成功能性連結。
     過去的研究發現太少或過量的壓力荷爾蒙均會造成海馬迴粒細胞的死亡，而一定量濃度的皮質固醇對於維持海馬迴粒細胞的生存亦扮演非常重要的角色。在摘除兩側的腎上腺後，海馬迴粒細胞在幾週後會逐漸死亡且造成認知功能的缺損。本實驗即利用雙側腎上腺摘除術建立動物模式，企圖了解海馬迴粒細胞在凋亡的過程中所產生的生理層面的改變。
      壓力荷爾蒙（包含皮質固醇，在老鼠稱為corticosterone，在人類稱為cortisol）為腎上腺皮質分泌激素，已知會參與並調控BK 離子通道的選擇性剪接。BK離子通道的孔道形成α次單元由單一基因 (Slo) 負責轉錄，含有STREX外顯子的剪接變異體之α次單元藉由加速神經細胞的再極化，增強過極化電位以及促進鈉離子通道自去活化狀態中回復可造成神經細胞重複激發，而先前的研究已發現過度的激發會對神經細胞產生興奮性毒殺作用。本實驗即探討BK 鉀離子通道選擇性剪接在海馬迴粒細胞凋亡的過程中所扮演的角色。 實驗結果發現，與對照組相比，雙側腎上腺摘除的老鼠海馬迴細胞中含有STREX外顯子的剪接變異體在mRNA含量上確實有改變，而BK 鉀離子通道蛋白質含量亦有所變化。由上述結果推測，含有STREX外顯子的剪接變異體含量可能與海馬迴粒細胞的凋亡機制有關。		zh_TW
dc.description.abstract (摘要) The hippocampus is a brain region central to learning and memory and is a key target of many neurological diseases that have dramatic cognitive consequences, including Alzheimer’s and other forms of dementia, stroke, epilepsy, and chronic stress. Hippocampal granule cells are one of the two cell pools that contain newborn neurons continuously generated from the subgranular zone in adult mammalian brains. The newborn neurons will migrate to the granule cell layer and integrate into preexisting neuron network. Previous studies have indicated that both an excessive and insufficient levels of stress hormones can lead to neuron death. Corticosterone, an adrenal stress hormone, is essential for the survival of granule cells. Bilateral removal of adrenal glands leads to extensive granule cell death over a period of several weeks and gradually causes cognitive deficits. To understand the mechanisms underlying the granule cell death in the hippocampal formation, adrenalectomy (ADX, removal of adrenal glands) was used to specifically eliminate granule cells in the hippocampus, and the subsequent physiological changes in the hippocampal neurons including dentate granule cells are investigated.
     
     Stress hormones (corticosterone in rats and cortisol in human) , secreted from the adrenal cortex regulate the alternative splicing of BK channels (big potassium, calcium-voltage activated potassium channels) in adrenal medulla. An inclusion of STREX (stress axis-regulated exon) exon in pore-forming α subunit encoded by Slo gene promotes repetitive firing by speeding action potential repolarization and augmenting the afterhyperpolarization, as well as facilitating sodium channels de-inactivation. In the present study, the role of BK channel alternative splicing in the ADX-induced granule cell death in the hippocampus was explored. The results indicate that BK channel alternative splicing was regulated by stress hormones in the hippocampus including dentate gyrus. The expression patterns of STREX variant in hippocampus were altered after granule cells death induced by ADX, whilst the expression of total slo gene was changes only in translational level. These observations suggest that the alternation in STREX abundance might be involved in the induction of dentate granule cell death.		en_US
dc.description.tableofcontents 中文摘要...I
     Abstract...II
     Table of contents...IV
     Figures...VI
     Abbreviations...VII
     1. Introduction...1
     1.1 The dentate gyrus...1
     1.2 Dentate granule cells...1
     1.3 Corticosterone and dentate granule cells...2
     1.4 Corticosterone receptors in the brain...3
     1.5 The mechanisms of adrenalectomy-induced dentate
      granule cell death...4
     1.6 Big conductance voltage-sensitive and Ca2+-activated
      potassium channel in the brain...5
     1.7 BK channel alternative splicing is regulated by
      corticosterone...7
     1.8 Hypothesis in this study...7
     2. Materials and Methods...9
     2.1 Animals and Surgery...9
     2.2 Samples collection...11
     2.3 Total RNA extraction and RT-PCR...12
     2.3.1 STREX/ZERO splice variants amplification...12
     2.3.2 Total Slo gene transcripts amplification...14
     2.4 Sample preparation and immunohistochemistry...15
     2.5 Primary cell culture and immunocytochemistry...18
     2.6 ELISA...20
     2.7 Data analysis... 21
     3. Results...22
     3.1 Attenuated body-weight gain and low plasma CORT
      levels were observed after ADX...22
     3.2 Quantitative Measurement of the Relative Abundance of
      STREX and ZERO Variants...26
     3.3 Relative abundance of STREX splice variant and total
      Slo gene transcripts in left hippocampi was not
      changed in prolonged ADX rats...28
     3.4 The alternation of STREX splice variant and total Slo
      transcripts was different in DG and left hippocampi
      after ADX...30
     3.5 The expression of BK channel α subunit protein was
      increased after ADX...33
     4. Discussion...36
     5. Conclusion…40
     6. References…41		zh_TW
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0097754001en_US
dc.subject (關鍵詞) BK離子通道zh_TW
dc.subject (關鍵詞) 海馬迴zh_TW
dc.subject (關鍵詞) 齒狀回zh_TW
dc.subject (關鍵詞) BKen_US
dc.subject (關鍵詞) Hippocampusen_US
dc.subject (關鍵詞) Dentate gyrusen_US
dc.title (題名) BK離子通道與海馬迴粒細胞死亡的相關性zh_TW
dc.title (題名) The relationship between BK channel alternative splicing and granule cell death in the hippocampusen_US
dc.type (資料類型) thesisen
dc.relation.reference (參考文獻) 1.Amaral DG, Scharfman HE, Lavenex P (2007) The dentate
      gyrus: fundamental neuroanatomical organization (dentate
      gyrus for dummies). Prog Brain Res 163:3-22.
     2.Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L (1993)
      mSlo, a complex mouse gene encoding "maxi" calcium-
      activated potassium channels. Science 261:221-224.
     3.Cameron HA, Gould E (1994) Adult neurogenesis is
      regulated by adrenal steroids in the dentate gyrus.
      Neuroscience 61:203-209.
     4.Cui J, Yang H, Lee US (2009) Molecular mechanisms of BK
      channel activation. Cell Mol Life Sci 66:852-875.
     5.De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998)
      Brain corticosteroid receptor balance in health and
      disease. Endocrine reviews 19:269-301.
     6.Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang
      L, Kotagal P, Luders HO, Shi J, Cui J, Richerson GB, Wang
      QK (2005) Calcium-sensitive potassium channelopathy in
      human epilepsy and paroxysmal movement disorder. Nat
      Genet 37:733-738.
     7.Faber ES, Sah P (2003) Calcium-activated potassium
      channels: multiple contributions to neuronal function.
      Neuroscientist 9:181-194.
     8.Gage FH (2000) Mammalian neural stem cells. Science
      287:1433-1438.
     9.Gotz J, Ittner LM (2008) Animal models of Alzheimer`s
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