生物谷報道：繼與人體冷知覺相關(guān)的基因"浮出水面"后,，科學(xué)家最近又確定了第一個直接與肌體癢知覺相關(guān)的基因,。這一發(fā)現(xiàn)有望為新型抗瘙癢藥物的開發(fā)開辟新的道路,。相關(guān)論文7月25日在線發(fā)表于《自然》雜志。
新發(fā)現(xiàn)的基因位于中央神經(jīng)系統(tǒng)，它可以產(chǎn)生"胃泌素釋放蛋白受體"（GRPR）。許多科學(xué)家都試圖研究GRPR基因與疼痛知覺的相關(guān)性,，并沒有人將它與瘙癢聯(lián)系起來。
在最新的研究中,，由美國華盛頓大學(xué)醫(yī)學(xué)院的華人遺傳學(xué)家Zhou-Feng Chen領(lǐng)導(dǎo)的小組對GRPR基因進(jìn)行了深入的研究,。他們發(fā)現(xiàn)，GRPR僅存在于一些脊髓神經(jīng)元中,，而這些神經(jīng)細(xì)胞能夠?qū)⑼春桶W的信號傳遞給大腦。進(jìn)一步的研究表明,，肌體產(chǎn)生疼痛知覺并不一定需要GRPR蛋白受體——失去GRPR基因的小鼠仍然能夠?qū)崃?、炎癥和機(jī)械傷害產(chǎn)生疼痛反應(yīng)。
研究人員隨后對GRPR基因突變的小鼠注射了組胺等癢誘導(dǎo)物質(zhì),，從而確定了GRPR與癢知覺的相關(guān)性,。他們發(fā)現(xiàn)，突變小鼠不會像正常小鼠一樣到處亂撓,。而當(dāng)正常小鼠被注射仿GRPR蛋白功能的物質(zhì)時,，它們抓狂地更厲害了。
許多疾病,，包括皮膚病和腫瘤都會引起慢性瘙癢,，這是一項(xiàng)頑疾，而新的發(fā)現(xiàn)無疑將為瘙癢患者帶來希望,。
美國加州大學(xué)戴維斯分校的神經(jīng)學(xué)家Earl Carstens和加拿大麥吉爾大學(xué)的遺傳學(xué)家Jeffrey Mogil都對新的研究成果表示了贊賞,，他們一致認(rèn)為GRPR是一個"不同尋常的分子標(biāo)靶"。
FIGURE 1. Expression pattern of GRP and GRPR in adult DRG and dorsal horn of the spinal cord.
a, GRP is detected in small to medium-sized DRG neurons by immunocytochemistry. b–e, Double-staining of GRP with peripherin (b), NF200 (c), IB4 (d) and CGRP (e) in DRGs. GRP (red) is localized in peripherin+ (green) DRG neurons (b). Double-staining of GRP (red) and NF200 (green) in adult mouse DRGs indicates that GRP and NF200 expression do not overlap (c). GRP is present in adult DRG neurons labelled with a CGRP antibody (green in e), but not with IB4 (green in d). Arrows indicate double-labelled neurons (b, e). f, GRP+ fibres (red) are located in the superficial dorsal horn; IB4 (green) marks lamina II inner layer (IIi) of the dorsal spinal cord. g, h, In situ hybridization (purple) showed that GRPR is present in the superficial dorsal horn of the spinal cord. Higher magnification of the dorsal horn is shown in h. Arrows indicate the GRPR+ neurons (h). Scale bars, 50 m (a, b, c, d, e, h); 100 m (f and g).
原文出處：
A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord
Yan-Gang Sun & Zhou-Feng Chen
doi:10.1038/nature06029
First paragraph | Full Text | PDF (2,182K) | Supplementary information
相關(guān)基因：
GRPR
Official Symbol GRPR and Name: gastrin-releasing peptide receptor [Homo sapiens]
Other Designations: GRP-preferring bombesin receptor
Chromosome: X; Location: Xp22.2-p22.13
Annotation: Chromosome X, NC_000023.9 (16051345..16081562)
MIM: 305670
GeneID: 2925
Order cDNA clone, Links
作者簡介：
Zhou-feng Chen, Ph.D.
Associate Professor of Anesthesiology
Washington University Pain Center
Basic Research Section
B.S. in Virology and Molecular Biology (1983)
Wuhan University, China
Ph.D. in Genetics (1994)
University of Texas Health Science Center, Houston
Postdoctoral training (1994-2000)
California Institute of Technology
Chen Lab Web Page
Research in the Chen Lab is focused on the molecular mechanisms underlying the assembly of the spinal dorsal horn circuitry. The spinal dorsal horn is a pivotal center for integrating and relaying pain-sensing signals (nociceptive) from the periphery to the brain. We have shown that Drg11, a paired homeobox transcription factor, is important for the projection of cutaneous sensory afferents in the spinal cord and Drg11 knockout mice exhibited significantly reduced responses to noxious stimuli. To further understand the role of Drg11, we have identified several upstream regulators and downstream targets of Drg11. One of upstream genes is Lmx1b, a LIM homeobox-containing gene. Analysis of Lmx1b knockout mice revealed its essential role in the differentiation of dorsal horn cells and in the projections of nociceptive afferents. To complement the mouse knockout approach, we recently established a novel mouse in utero electroporation technique, which for the first time allows us to overexpress the genes in the dorsal spinal cord conveniently. In addition, we are using RNAi (RNA interference) technology, combined with in utero electroporation, to "knockdown" the genes of interest in the mouse dorsal spinal cord to assess their function.
Another area of focus is to identify the dorsal horn-specific genes by differential screening. A genome-wide microarray approach is being used to identify genes that may involve chronic pain and/or dorsal horn development. Cre/LoxP system is also being used to generate the dorsal spinal cord conditional knockouts. These molecular, cellular and genetic studies should not only gain insights into the fundamental mechanisms underlying the development of the dorsal spinal cord but also reveal potential sites of drug actions on central pain pathways and thus aid in the new pharmacological strategies for spinal cord injury and pain relief.
Recent publications
Zhao, Z, Chiechio, S, Sun, Y, Zhang, K, Zhao, CS, Scott, M, Johnson, RL, Deneris, ES, Renner, KJ, Gereau, RW, and Chen, ZF (2007) Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. Journal of Neuroscience 27(22): 6045-6053.
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Rebelo S, Chen ZF, Anderson DJ and Lima D (2006) Involvement of DRG11 in the development of the primary afferent nociceptive system Mol. Cell. Neuroscience 33(3): 236-246.
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Zhao, Z.Q., Scott, M., Chiechio, S., Wang, J.-S., Renner, K.J., Gereau, R.W., Johnson, R.L., Deneris, E.S., and Chen, Z.F. (2006) Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system show normal locomotor activity. Journal of Neuroscience 26(49):12781-12788.
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Li MZ, Wang JS, Jiang DJ, Xiang CX, Wang FY, Zhang KH, Williams PR and Chen ZF (2006) Molecular mapping of developing dorsal horn-enriched genes by microarray and dorsal/ventral subtractive screening. Developmental Biology 292: 555-564.
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Erzurumlu RS, Chen ZF and Jacquin MF (2006) Molecular determinants of the face map development in the trigeminal brainstem. The Anatomical Record Part A 288A: 121-134.
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Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko S, Jia YG, Shum F Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia L, Chen ZF, Auberson YP, Kaang BK and Zhuo M (2005) Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. The Journal of Neuroscience 25(48): 11107-11116.
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Ding YQ, Kim JY, Xu YS, Rao Y, and Chen ZF (2005) Ventral migration of early-born neurons requires DCC and is essential for the projections of primary afferents in the spinal cord. Development 132: 2047-2056.
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Ding YQ, Xiang CX, and Chen ZF (2005) Generation and characterization of the PKCy-Cre Mouse Line. Genesis 43: 28-33.
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Dunston J, Reimschisel T, Ding YQ, Sweeney E, Johnson R, Chen ZF, and McIntosh I (2005) A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression. European Jounal of Human Genetics 13(3): 330-5.
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Ren X, Ming G, Xie Y, Sun D, Zhao Z, Feng Z, Wang Q, Shim S, Chen ZF, Song H, Mei L and Xiong W. (2004) Focal adhesion kinase in netrin-1 signaling. Nature Neuroscience 7(11): 1204-12.
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Ding YQ, Yin J, Kania A, Zhao ZQ, Johnson RL, and Chen ZF (2004) Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord. Development 131(15): 3693-3703.
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Ding YQ, Yin J, Xu HM, Jacquin MF, and Chen ZF (2003) Formation of whisker-related principal sensory nucleus-based lemniscal pathway requires a paired homeodomain transcription factor, Drg11. J Neuroscience 23(19): 7246-54.
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Ding YQ, Marklund U, Yuan W, Yin J, Wegman L, Ericson J, Deneris E, Johnson RL, and Chen ZF (2003) Lmx1b is essential for the development of serotonergic neurons. Nature Neuroscience 6(9): 933-8.
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Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LF, and Zhuo M (2002) Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36(4): 713-26.
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Li YC, Kong J, Wei M, Chen ZF, Liu SQ, and Cao, LP (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 110(2): 229-38.
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Chen ZF, Rebelo S, White F, Malmberg AB, Baba H, Lima D, Woolf CF, Basbaum AI, and Anderson DJ (2001) The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory affernet fibers to the dorsal spinal cord. Neuron 31(1): 59-73.
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Wei F, Wang GD, Kerchner GA, Kim SJ, Xu HM, Chen ZF, and Zhuo, M (2001) Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nature Neuroscience 4(2): 164-9.
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Labarca C, Schwarz J, Deshpande P, Schwarz S, Nowak MW, Fonck C, Nashmi R, Kofuji P, Dang H, Shi W, Fidan M, Khakh BS, Chen Z, Bowers BJ, Boulter J, Wehner JM, Wehner JM, Lester HA (2001) Point mutant mice with hypersensitive (alpha) 4 nicotinic receptors
