生物谷報道：俄亥俄州哥倫布市--一項新的研究表明成熟腦細胞表面的三種特定蛋白量的增加可促使細胞產(chǎn)生新的生長延伸.該研究探討了小鼠腦神經(jīng)細胞上的三個相關(guān)的受體蛋白:GPR3, GPR6和GPR12.當(dāng)研究人員增加這三種蛋白的量后,細胞生長延伸比蛋白水平正常時的神經(jīng)細胞的生長延伸長三倍、延伸速度比對照細胞快4-8倍. "俄亥俄州立大學(xué)醫(yī)學(xué)中心的項目主持人Yoshinaga Saeki說."我們的研究結(jié)果顯示,這三種蛋白可能是用于治療中風(fēng),腦和脊髓損傷及神經(jīng)退行性疾病的重要靶點“該研究刊登在4月6日的《生物化學(xué)》雜志上.
這些蛋白量的增加與神經(jīng)細胞cAMP內(nèi)的一種重要的信號分子的水平的增加有關(guān).這個分子在調(diào)控神經(jīng)細胞生長、分化和生存, 及傳輸神經(jīng)沖動的軸突的再生中起著關(guān)鍵作用.隨著哺乳動物神經(jīng)細胞的成熟,其細胞內(nèi)的cAMP水平下降,這是解釋為什么成熟神經(jīng)細胞受損的軸突不能再生的部分原因.神經(jīng)外科副教授,俄亥俄州州立dardinger神經(jīng)腫瘤及神經(jīng)科學(xué)實驗室主管Saeki聲稱."我們的發(fā)現(xiàn)為cAMP在軸突生長中起著重要作用這一觀點提供了更多證據(jù),并顯示這些受體蛋白可能在調(diào)節(jié)神經(jīng)細胞cAMP的產(chǎn)生中起主要作用.”
該研究的第一作者Shigeru Tanaka是Saeki所在實驗室的一名博士后研究員. 在本項研究中,他與同事從小鼠與大鼠腦組織神經(jīng)母細胞瘤中取得神經(jīng)細胞,使之在培養(yǎng)基中生長以了解更多關(guān)于這三種蛋白及其調(diào)控cAMP生長中的作用.他們向這些細胞中注入三種基因以增加這三種蛋白的含量水平, 然后用一種被稱為核糖核酸干擾的實驗室技術(shù)關(guān)閉這三種蛋白的產(chǎn)生.上述三個蛋白分子中GPR3在神經(jīng)細胞中最為豐富,而GPR12刺激神經(jīng)細胞延伸的作用最強. 研究表明阻斷GPR3的產(chǎn)生就大大減慢了神經(jīng)細胞的生長速度,研究者們通過修復(fù)GPR3或GPR12的產(chǎn)生扭轉(zhuǎn)了這種效應(yīng).三種蛋白質(zhì)的含量水平高也與較高水平的cAMP有關(guān), 同時GPR6和GPR12能增加兩倍到三倍的水平.
"總的來說,"Saeki說, "我們的研究結(jié)果顯示,這三種蛋白能加快神經(jīng)細胞的生長即使在抑制分子的存在下也是如此,我們迫切希望能找出可以在臨床前中風(fēng)或脊髓損傷動物模型身上重現(xiàn)此結(jié)果的方法. "
原文出處：
Shigeru Tanaka, Ken Ishii, Kazue Kasai, Sung Ok Yoon, and Yoshinaga Saeki
Neural Expression of G Protein-coupled Receptors GPR3, GPR6, and GPR12 Up-regulates Cyclic AMP Levels and Promotes Neurite Outgrowth
J. Biol. Chem. 2007 282: 10506-10515. First Published on February 6, 2007; doi:10.1074/jbc.M700911200 [Abstract] [Full Text] [PDF] [Supplemental Data]
相關(guān)基因：
GPR3
Official Symbol: GPR3 and Name: G protein-coupled receptor 3 [Homo sapiens]
Other Aliases: ACCA
Other Designations: OTTHUMP00000043209; adenylate cyclase constitutive activator
Chromosome: 1; Location: 1p36.1-p35
MIM: 600241
GeneID: 2827
GPR6
Official Symbol: GPR6 and Name: G protein-coupled receptor 6 [Homo sapiens]
Chromosome: 6; Location: 6q21
MIM: 600553
GeneID: 2830
GPR12
Official Symbol: GPR12 and Name: G protein-coupled receptor 12 [Homo sapiens]
Other Aliases: GPCR12, GPCR21, MGC138349, MGC138351
Chromosome: 13; Location: 13q12
MIM: 600752
GeneID: 2835
作者簡介：
Yoshinaga Saeki, M.D., Ph.D.
Associate Professor
Department of Neurological Surgery
Ph.D.: Osaka University
Postdoctoral Training: Massachusetts General Hospital and Harvard Medical School
PHONE: (614) 292-3804
FAX: (614) 688-4882
E-MAIL: [email protected]
Link to NLM PubMed publications list for Yoshinaga Saeki (last 10 years)
Research Area:
Gene- and cell-based therapy for neurological disorders Development and applications of viral vectors
Current Research:
My laboratory is developing therapeutic strategies for neurological disorders. We are engaged in three major ongoing projects that employ multidisciplinary research techniques.
Developing and applying herpes simplex virus (HSV)-based amplicon vectors for gene therapy and neuroscience research; HSV amplicon vectors are plasmid-based, high-capacity vectors that have full HSV infection machinery.
identifying and characterizing cellular and immunological mechanisms that regulate HSV amplicon-mediated transgene expression
developing “indicator” HSV amplicon vectors to monitor various cellular activities
genetic engineering of neuronal cells using “regulatable” HSV amplicon vectors
Development and applications of engineered, oncolytic HSV vectors for brain tumor therapy.
identifying and characterizing cellular and immunological mechanisms that interfere with oncolytic activities of replication-conditional HSV vectors
developing novel oncolytic virotherapies that target brain tumor stem cells
Studying the roles of three related orphan G protein-coupled receptors, GPR3, GPR6, and GPR12, in the mammalian central nervous system
defining the functions of GPR3, GPR6, and GPR12 using knockout mice and cultured primary neurons
defining the roles of GPR3, GPR6, and GPR12 in neurological disorders, such as spinal cord injury and stroke
Techniques:
Molecular biology: cloning of genes; construction of viral vectors; cloning and engineering viral genomes; BAC engineering; ChIP-PCR; pulsed field-gel electrophoresis (PFGE); GFP and epitope tagging; and purification of His-tagged proteins. Cell Biology: transfection of cultured cells; RNAi; immunocytochemistry; FACS analysis; immunoblotting; immunoprecipitation; and primary neural cultures. Imaging: confocal microscopic imaging; time-lapse fluorescent microscopic imaging; and in vivo bioluminescence imaging. Transgenic mice and small animal surgery: in vivo gene transfer.
