Molecular Evolution and Systems Biology Study of Hypoxia-Inducible Signaling Pathway in Embryonic Development

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基本資料

Project title

Code/計畫編號

NSC99-2627-B019-005

Translated Name/計畫中文名

從分子演化及系統生物學角度探討胚胎發育時期低氧細胞訊息路徑的功能與調控機制---總計畫及子計畫四:斑馬魚發育時期HIFs的訊息路徑與生物功能區別

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=2151194

Year

2010

Start date/計畫起

01-08-2010

Expected Completion/計畫迄

01-07-2011

Bugetid/研究經費

1500千元

ResearchField/研究領域

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。在正常氧濃度情況下，HIFα會受到專一性氫氧酶PHD 與FIH 作用，造成失活與水解。在低氧情況下，因為PHD 與FIH 失去活性，造成HIFα結構穩定化且可與ΑRNT 結合，由C-TAD 與p300 作用來啟動目標基因的表現。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survivin 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。在本計劃中，我們想要以斑馬魚、海膽及文昌魚為模式生物，結合生物資訊、基因體/蛋白體學及各項胚胎操作、分子生物與生化分析工具，從基因調控網路、訊息傳遞、蛋白結構、細胞生理與分子演化等不同的層面分為4 項主題來探討發育時期低氧訊息路徑的生物功能與調控機制。這些主題分別為：1. 斑馬魚發育時期HIFα 的訊息路徑與生物功能區別；2. 胚胎發育時期氧依賴型氫氧酶PHD 與FIH 的生化特性與功能；3. 從海膽與文昌魚的胚胎發育探討低氧訊息路徑的演化歷史，以及4. 跨物種低氧訊息相關基因比對及時序性胚胎低氧訊息網路建構。我們預期這項研究結果將可協助我們瞭解胚胎發育期間低氧訊息路徑基因調控網路以及它們的穩定調節機制。" "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. In normal oxygen concentration, the HIFα factors are hydroxylated by PHD and FIH enzymes, which in turn will be destabilized by ubiquitination. In hyoxia stress, the enzymatic activities of PHD and FIH will be inhibited and the HIFα will be stabilized, which in turn will activate the downstream target genes. 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 combine all kinds of bioinformatics, genomics, proteomics tools and various molecular biology and biochemical analysis tools to study the functions and genetic regulatory networks of hypoxia-related signaling pathways in zebrafish, sea urchin and amphioxus embryos. Specifically, the research works will be focus on the following subjects: 1. the function and stability control of HIF factors in zebrafish embryo, 2. characterization of PHD and FIH activities in zebrafish embryos and their roles in hypoxia signaling pathway, 3. deciphering the evolutionary history of hypoxia signaling pathway and the function of HIF in the development of sea urchin and amphioxus, 4. developing a novel web system which can automatically identify novel HIF target genes based on Gene Ontology (GO) annotation and the known information of consensus transcription binding factors appeared in the oxygen-regulated elements. We expect this integrated study will elucidate the conservation and function of hypoxia signaling networks in developing embryos."

Keyword(s)

斑馬魚
低氧誘發蛋白HIF1/HIF2a
細胞抗凋亡蛋白survivin
神經初始細胞
細胞凋亡
細胞分化
血球生成
血紅素
zebrafish
HIF1a
HIF2a
survivin
neural progenitor cells
apoptosis
differentiation
erythropoiesis
heme

DSpace CRIS

Molecular Evolution and Systems Biology Study of Hypoxia-Inducible Signaling Pathway in Embryonic Development

基本資料

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