张旭博士

生物谷

Xu Zhang, Ph.D.

Rm 219, ION Building
Institute of Neuroscience
Chinese Academy of Sciences
Shanghai 200031, China
Email: xu.zhang@ ion.ac.cn
Phone: 86-21-5492 1761
lab homepage

Co-Principal Investigator
Lan Bao, M.D.
baolan@ ion.ac.cn

1985年9月-1987年4月第四军医大学神经生物学教研室助教
1987年5月-1988年1月瑞典Stockholm 大学超微结构研究室访问学者
1988年2月-1990年9月第四军医大学神经生物学教研室助教
1990年10月-1994年7月瑞典卡罗琳斯卡医学院神经科学系博士研究生，获博士学位
1994年8月-1994年11月第四军医大学神经科学研究所讲师
1994年12月-1997年11月第四军医大学神经科学研究所副教授
1997年12月-1999年11月第四军医大学神经科学研究所教授，博士生导师
1999年至今中国科学院神经科学研究所课题组长，研究员

一、背根节神经元基因表达水平的长时程可塑性研究
为了全面了解外周神经损伤后初级感觉神经元（背根节神经元）基因表达水平的变化，我们首先建立了大鼠的基因表达文库，运用基因芯片技术比较了正常大鼠与外周神经损伤后2天、7天、14天和28天大鼠背根节基因表达水平的变化。通过检测7523条基因，并用RT-PCR和分子原位杂交技术进行证实和细胞定位，发现有122条基因与51条EST的表达量有显著性变化，包括神经肽、受体、离子通道和信号转导分子等。同时进一步发现部分基因是或可能成为镇痛药的靶点。本研究将进一步对在外周神经损伤和外周炎症时发生调节的功能不清和新基因进行研究。

二、背根神经节与脊髓背角结构上的长时程可塑性研究
外周神经切断诱导初级传入的Aβ纤维在脊髓的投射由III-IV层长入I-II层，此结果被认为是神经源性痛的解剖学基础之一。然而，我们通过标记背根神经节小神经元中特异性的物质，结合神经切断前霍乱毒素B亚单位（CTB）束路追踪技术，发现坐骨神经切断后只有少量Aβ纤维长入内II层，外II层和I层中没有观察到长芽的纤维。而少量长芽的纤维在II层可形成突触连接，有可能形成异常的神经回路，可能是神经病理性痛的成因之一。外周神经损伤条件下异常神经网络的形成与痛敏直接相关，我们将对异常神经网络和其分子机制进行进一步研究。

三、背根神经节神经元的短时程可塑性研究
阿片受体在痛觉传递中起十分重要的作用。在正常情况下，m阿片受体主要位于初级感觉神经元的膜上，d阿片受体则主要位于初级感觉神经元的胞浆内，且位于胞浆内的大致密芯泡膜上，这些大致密芯泡内含有P物质和降钙素基因相关肽等神经肽。我们的研究证明该受体是通过在神经肽分泌泡的特异性分布，形成特异的正反馈调控机制，即激动d阿片受体导致该受体在极短时间内进一步嵌入胞膜，保持神经元对阿片物质的敏感性，能够使神经肽在短时间内从神经元中排空，同时减少d阿片受体的储存。这些结果对阿片受体介导的疼痛治疗可以提供一种新的观点，炎性疼痛的治疗可以不仅激活m受体，而且或许需阻断d受体。进一步的研究将集中在受体分选、运输和上膜及神经肽分泌的分子机制。
以上研究一方面揭示了神经元基本活动的分子和细胞机制；另一方面为疼痛的发生和发展、神经的再生提供了理论基础，一些与痛的发生和发展有关的重要机制和一些重要分子的发现，为寻找新的镇痛方案和新药开发提供重要的线索。

Dr. Xu Zhang graduated from Fourth Militory Medical University in Xi'an, China in 1985, and obtained his Ph.D. at Department of Neuroscience, Karolinska Institute, Sweden in 1994. He joined ION in 1999 and is now an investigator and head of the Laboratory of Sensory System. His main interest is to study the molecular and cellular mechanisms involved in the regulation of sensory signaling in the dorsal root ganglion neurons and spinal dorsal horn neurons, especially the mechanisms of chronic pain and nerve regeneration following peripheral nerve injury.

Research Interests
	We are interested in the basic mechanisms underlying gene activation and the sorting, transport and targeting of proteins in sensory neurons. Our long-term research goal is to understand the neurobiological basis of chronic pain and nerve regeneration and to identify rational therapeutic approaches in curing disfunctions in human sensory systems. From gene regulation and protein trafficking to neuronal modulation and neuropathic pain. Neuropeptides play important roles in the transmission and modulation of pain sensation. We are thus interested in the gene regulation, processing and trafficking of neuropeptides and their receptors in sensory neurons under physiological or pathological conditions. Since the distribution of membrane receptors and ion channels in the axons and dendrites are susceptible to modulation and such modulation has direct consequences in the function and plasticity of synaptic transmission, we are focusing on the correlation between the changes in the distribution of receptors and ion channels in the pre- and postsynaptic membranes and the functional modulation of primary sensory neurons and their synaptic properties. For examples, peripheral nerve injury and inflammation cause dramatic changes in the functions of dorsal root ganglion (DRG) neurons, often leading to chronic pain. We have thus focused our studies on the plasticity of DRG and spinal cord neurons after peripheral nerve injury and inflammation, e.g., changes in gene expression, cellular localization and functions of neuropeptides and their receptors, transmitters and their receptors, as well as ion channels and related channel modulators. In addition, we are also examining changes in physiological and anatomical changes in the neural circuits in the dorsal horn of the spinal cord in animal models of neuropathic and inflammatory pain.

	Ongoing Projects
	Long-term plasticity of DRG neurons at the level of gene expression. To determine global alterations in neuronal gene expression following nerve injury, we have carried out cDNA array analysis on cDNA libraries of lumbar DRGs of normal rats and of rats 14 days after peripheral axotomy. Of 7523 genes and expression sequence tags (ESTs) examined, marked alteration in the expression of 122 genes and 51 ESTs was found. These genes encompass a large number protein families, including neuropeptides, membrane receptors, ion channels, signal transduction molecules, and synaptic vesicle proteins. Of particular interest is the upregulation of ¦Ã-aminobutyric acidA receptor ¦Á5 subunit, peripheral benzodiazepine receptor, nicotinic acetylcholine receptor ¦Á7 subunit, P2Y1 purinoceptor, sodium channel ¦Â2 subunit and calcium channel ¦Á2¦Ä-1 subunit. Our finding reveals a dynamic and complex change in the gene expression in DRG neurons after peripheral axotomy. We are also examining changes in the gene expression of dorsal horn neurons using similar cDNA array analysis. Long-term structural plasticity in DRG and spinal cord. Peripheral axotomy-induced sprouting of thick myelinated afferents (A-fibers) from laminae III-IV into laminae I-II of the spinal cord has been postulated to be the structural basis of neuropathic pain. However, our recent study showed that axotomy-induced sprouting from deeper to superficial layers is much less pronounced than previously assumed. This conclusion is based on our labeling studies using cholera toxin B subunit (CTB), a neuronal tracer used to demonstrate the sprouting of A-fibers in several earlier studies. We found that CTB could label unmyelinated afferents (C-fibers) in lamina II and thin myelinated afferents in lamina I, when it is applied after peripheral axotomy. In an attempt to label large DRG neurons and A-fibers selectively, CTB was applied four days before axotomy ('pre-injury-labeling'), and sprouting was monitored after axotomy. We find that only a small number of A-fibers sprouted into inner lamina II, a region normally innervated by C-fibers, but not into outer lamina II or lamina I. Neuropeptide Y (NPY) is found in these sprouts in inner lamina II, an area very rich in Y1 receptor-positive processes. Although limited in numbers, this large NPY immunoreactive DRG axon sprouting into the inner lamina II may account for a functional circuitry involved in neuropathic pain. Short-term plasticity DRG and spinal cord neurons. Neurotransmitter receptors and ion channels are important for the regulation of pain transmission and pain treatment. Our study is focused on the cellular and molecular mechanisms involving in the trafficking of membrane receptors and channels in primary sensory neurons and the dorsal spinal cord neurons, and the regulation and changes in trafficking mechanisms under physiological and pathological conditions. We believe that the sensitivity of the neurons can be modified by changing the plasma membrane composition of receptors and channels within the time scale of seconds to minutes in response to different extracellular stimuli.

	Publications
	Zhang, K., Xiao, H., Lu, P., Shi, J., Li, G., Wang, Y., Han, S., Zhang, F., Lu, Y., Zhang, X., and Xu., X. (2004) Differential Gene Expression after Complete Spinal Cord Transection in Adult Rats: An Analysis Focused on a Subchronic Post-Injury Stage. Neurosci. 128: 375-388. Yang, L., Zhang, F., Huang, F., Lu, Y., Li, G., Bao, L., Xiao, H., and Zhang, X. (2004) Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur. J. Neurosci. 19, 871-883. Xu, N., Bao, L., Fan, H., Bao, G., Pu, L., Lu, L., Wu, C., Zhang, X., and Pei, G.(2003) Morphine Withdrawal Increases Glutamate Uptake and Surface Expression of Glutamate Transporter GLT1 at Hippocampal Synapses. J. Neurosci., 23: 4775-4784. Bao, L., Jin, S., Zhang, C., Cai, H., Xu, Z., Wang, L., Xiao, H., Ning, F., Zhang, F., Lu, Y., Hokfelt, T., Zhou, Z., and Zhang, X. (2003) Activation of delta-opioid receptors induces receptor insertion and neuropeptide secretion. Neuron, 37,121-133 Bao, L., Wang, H., Cai, H., Tong, Y., Jin, S., Lu, Y., Grant, G., Hokfelt, T., and Zhang, X.(2002) Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Eur. J. Neurosci. 16: 175-185 Li, G., Wo, Y., Zhong, M., Zhang, F., Bao, L., Lu, Y., Huang, Y., Xiao, H., and Zhang, X. (2002) Expression of fibroblast growth factors in rat dorsal root ganglion neurons and regulation after peripheral nerve injury. NeuroReport 13: 1903-1907 Xiao, H., Huang, Q., Zhang, F., Bao, L., Lu, Y., Guo, C., Yang, L., Huang, W., Fu, G., Xu, S., Cheng, X., Yan, Q., Zhu, Z., Zhang, X., Chen, Z., Han Z., and Zhang, X. (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc. Natl. Acad. Sci. USA. 99: 8360-8365. C. L. Stucky, M. S. Gold and X. Zhang (2001) Mechanisms of pain. Proc. Natl. Acad. Sci. USA. 98: 11845-11846