Function of Hif2a on Apoptosis and Differentiation during Zebrafish Embryonic Stage

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Project title

Code/計畫編號

NSC99-2313-B019-008-MY3

Translated Name/計畫中文名

斑馬魚胚胎時期HIF2a蛋白控制細胞凋亡與細胞分化的機制

Project Coordinator/計畫主持人

Chin-Hwa Hu

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

Department of Bioscience and Biotechnology

Website

https://www.grb.gov.tw/search/planDetail?id=2395123

Year

2012

Start date/計畫起

01-08-2012

Expected Completion/計畫迄

01-07-2013

Bugetid/研究經費

1500千元

ResearchField/研究領域

海洋科學
生物技術(理)

低氧誘發蛋白hypoxia-inducible factors是屬於bHLH-PAS家族的成員，其本身是由對氧濃度相當敏感的alpha次單元和另一個相當穩定的beta次單元（ARNT）所組合而成。HIF在維持細胞內氧恆定性扮演了關鍵角色，在面臨缺氧環境下負責調控細胞內的代謝、凋亡、增生以及血球新生和血管增生等細胞生理活性。在斑馬魚中共有三種的HIFα基因，分別為HIF1α、HIF2α與HIF3α。我們最近的研究發現在斑馬魚胚胎中，HIF2α在維護中樞神經細胞的生存與分化的過程扮演了相當重要與獨特的功能。弱化HIF2α會影響胚胎內survivin1與survivin2的表現，使得中樞神經的細胞大量凋亡，此外也同時造成神經細胞停止分化，大部分神經先驅細胞均停留在未分化階段。在這項計畫中我們將更深入的探討HIF2α在斑馬魚胚胎中控制神經細胞凋亡與分化的機制以及在胚胎時期控制HIF2α蛋白穩定性的機制。在保護細胞避免凋亡的機制方面，我們想要瞭解HIF2α與控制細胞凋亡相關基因間的關連性。在神經細胞的分化方面，我們想探討HIF2α是否與控制細胞週期脫離的關鍵性基因相關。在HIF2α結構穩定性方面，我們想探討是否在胚胎時期其蛋白結構的安定性與PHD的活性受到限制有關，以及其形成的原因。我們將利用各種分子生物與細胞生化的實驗方法從基因調控、DNA辨識、蛋白結構、細胞生理與基因網路的不同層面，來探討HIF2α在胚胎內的功能。 Hypoxia-inducible factors (HIFs) are heterodimeric basic-helix-loop- helix-PAS transcription factors consisting of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit, also known as ARNT. HIFs play key roles in oxygen homeostasis by regulating the genes that are involved in a number of cellular processes, including glucose uptake and metabolism, erythorpoiesis, angiogenesis, apoptosis and cell proliferation. There are three HIFα genes in zebrafish, including HIF1α, HIF2α and HIF3α. Recently we found that HIF2α has critical and unique role in neural cell protection and differentiation. HIF2α knockdown reduced survivin 1 and survivin 2 transcriptions and caused apoptosis. Most of CNS cells did not exit from cell cycle and stayed in undifferentiated stage. In this research plan, we would like to investigate the functions of HIF2α in CNS cell differentiation and apoptosis as well as the mechanism of HIF2α stabilization. Specifically, we will focus on the following aspects: how does HIF2α control apoptotic and antiapoptotic genes (such as p53, IAPs and antioxidant enzymes), how does HIF2α control cell cycle exit (such as cdk inhibitors and cyclins at G1 checkpoint) and how is HIF2α stabilized in embryo (such as PHD inhibition and mitochondria-mediated ROS accumulation). In brief, the function of HIF2α in embryo will be studied through gene expression, protein-DNA interaction, protein stability, cell physiology and genetic network aspects.

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Function of Hif2a on Apoptosis and Differentiation during Zebrafish Embryonic Stage

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