探討丙戊酸 (Valporic acid) 於肌肉細胞中活化 Oct4 promoter 的機制 ; Defining the mechanism of valproic acid enhanced Oct4 promoter activation in myogenic cells

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Title:	探討丙戊酸 (Valporic acid) 於肌肉細胞中活化 Oct4 promoter 的機制;Defining the mechanism of valproic acid enhanced Oct4 promoter activation in myogenic cells
Authors:	鄧涵方;Han-fang Teng
Contributors:	生命科學研究所
Keywords:	誘導型多能性幹細胞;肌肉細胞;丙戊酸;Valporic acid;myogenic cells;Induced pluripotent stem cells
Date:	2010-07-29
Issue Date:	2010-12-08 14:41:52 (UTC+8)
Publisher:	國立中央大學
Abstract:	多能性的胚胎幹細胞具有能夠持續生長以及分化成三個胚層細胞的能力。希望能夠利用這些幹細胞去治癒目前針對傳統醫療方式無法治癒的疾病，但其數量及種類稀少，且在來源上引起許多道德上的爭議；甚至移植於人體內會引起免疫排斥作用的干擾。Takahashi and Yamanaka 於 2006 年藉由細胞內大量表現 Oct4, Sox2, Klf4 及 c-Myc 成功將老鼠胚胎纖維母細胞誘導成具有多能特性，類似於幹細胞的 iPS cells。雖然 iPS cells 的形成開啟了利用自體細胞進行治療的可能，但仍然存在許多問題尚待解決，例如：利用病毒帶入質體的方式可能會導致插入突變的產生，以及 re-programming 的效率過低等等…。而在近年有文獻指出許多小分子化合物，像是 VPA、Bix-01924、AZA…等，可有效提升 re-programming 的效率，而我們的研究集中在 VPA 這個 HDAC 的抑制劑。在我們的研究當中發現 VPA 能夠在 P19 及 C2C12 細胞中增強 Oct4 1.9k promoter 的活性，因此希望探討其相關機制。根據實驗結果推測，VPA 可藉由徵召特定的轉錄因子至 Oct4 promoter 上活化其表現。接著進一步找出其結合位，利用 deletion 及突變 Oct4 promoter 上 hormone receptor-binding site 觀察 VPA 活化的效用是否會減弱甚至消失。而在未來的實驗當中希望能找出確切影響的因子，以及結合許多不同的小分子化合物來達到有效提升 reprogramming 效率的成果。 Embryonic stem (ES) cells have the ability to grow indefinitely while maintaining pluripotency, the ability to differentiate into cells of all three germ layers. They can be used to treat a host of diseases, but there are ethical issues about their sources and problem of the possible immune rejection by the host. In 2006, Takahashi and Yamanaka successfully reprogrammed mouse embryonic fibroblasts to induced pulripotent stem cells (iPS cells) by over-expressing Oct4, Sox2, Klf4 and c-Myc. Although iPS cells open the possibility of autologous stem cell for therapy, it still has some risks, such as insertion mutagenesis and low re-programming efficiency, to be overcome. In 2008, a study showed that some small compounds, such as a histone deacetylase inhibitor called VPA, could increase the reprogramming efficiency. In our study we found that VPA could enhance the Oct4 2k promoter activity both in P19 and C2C12 cells, and it was of interest to define the mechanism. We proposed that VPA might recruit a transcription factors to the Oct4 promoter to activate its activity. We made deletion mutants of the Oct4 promoter and also mutated the hormone receptor-binding site on Oct4 promoter to see whether the VPA activaty will be abrogated. We confirmed that HRE was important in the mechanism of VPA activated the Oct4 promoter. In the future, we want to combine different small compounds to see if the iPS cells reprogramming efficiency will be increased.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

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