生物谷报道：继与人体冷知觉相关的基因"浮出水面"后，科学家最近又确定了第一个直接与肌体痒知觉相关的基因。这一发现有望为新型抗瘙痒药物的开发开辟新的道路。相关论文7月25日在线发表于《自然》杂志。
新发现的基因位于中央神经系统，它可以产生"胃泌素释放蛋白受体"（GRPR）。许多科学家都试图研究GRPR基因与疼痛知觉的相关性，并没有人将它与瘙痒联系起来。
在最新的研究中，由美国华盛顿大学医学院的华人遗传学家Zhou-Feng Chen领导的小组对GRPR基因进行了深入的研究。他们发现，GRPR仅存在于一些脊髓神经元中，而这些神经细胞能够将痛和痒的信号传递给大脑。进一步的研究表明，肌体产生疼痛知觉并不一定需要GRPR蛋白受体——失去GRPR基因的小鼠仍然能够对热量、炎症和机械伤害产生疼痛反应。
研究人员随后对GRPR基因突变的小鼠注射了组胺等痒诱导物质，从而确定了GRPR与痒知觉的相关性。他们发现，突变小鼠不会像正常小鼠一样到处乱挠。而当正常小鼠被注射仿GRPR蛋白功能的物质时，它们抓狂地更厉害了。
许多疾病，包括皮肤病和肿瘤都会引起慢性瘙痒，这是一项顽疾，而新的发现无疑将为瘙痒患者带来希望。
美国加州大学戴维斯分校的神经学家Earl Carstens和加拿大麦吉尔大学的遗传学家Jeffrey Mogil都对新的研究成果表示了赞赏，他们一致认为GRPR是一个"不同寻常的分子标靶"。
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).
原文出处：
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
相关基因：
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
作者简介：
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
