SCI 文 章
1. Leyu Shi , Shoufang Gong, Zhongmin Yuan , Chi Ma, Yanling Liu, Chuanfu Wang , Wenming Li, Rongbiao Pi, Shoujian Huang, Ruzhu Chen , Yifan Han , Zixu Mao, and Mingtao Li(通訊作者). Activity deprivation-dependent induction of the proapoptotic BH3-only protein Bim is independent of JNK/c-Jun activation during apoptosis in cerebellar granule neurons. Neurosci Lett. 2005, 375：7－12.
2. Wenya Wang, Chi Ma, Zixu Mao and Mingtao Li. (通訊作者). JNK inhibition as a potential strategy in treating Parkinsons’s disease. Drug News Perspect, 2004, 17(10):646-54.
3. Wenya Wang, Leyu Shi, Yuanbin Xie, Chi Ma, Wenming Li, Xingwen Su, Shoujian Huang, Ruzhu Chen, Zhenyu Zhu, Zixu Mao, Yifan Han and Mingtao Li. (通訊作者). SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Neurosci Res 2004；48:195-202
4. Yuanbin Xie, Yanling Liu, Chi Ma, Zhongmin Yuan, Wenya Wang, Zhenyu Zhu, , Guoquan Gao, Xianguo Liu, Hengxin Yuan, Ruzhu Chen, Shoujian Huang, Xuelan Wang, Xiaonan Zhu, Xuemin Wang, Zixu Mao and Mingtao Li (通訊作者). Indirubin-3′-oxime inhibits c-Jun NH2-terminal kinase: anti-apoptotic effect in cerebellar granule neurons. Neurosci Lett. 2004, 367:355-359.
5. Rongbiao Pi, Wenming Li Nelson T.K.Lee, Hugh H.N.Chan, Yongmei Pu, Ling Nga Chan, Nikolaus J.Sucher, Doanld C. Chang, Mingtao Li and Yifan Han. Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem. 2004, 91:1212-1230. Wenya Wang, Chi Ma, Zixu Mao and Mingtao Li. (通訊作者). JNK inhibition as a potential strategy in treating Parkinsons’s disease. Drug News Perspect, 2004, 17(10):646-54.
6. Wenming Li, Rongbiao Pi, Hugh H. N. Chan, Hongjun Fu, Nelson T. K. Lee, Hing Wai Tsang, Yongmei Pu, Donald C. Chang, Chaoying Li, Jialie Luo, Keming Xiong, Zhiwang Li, Hong Xue, Paul R. Carlier, Yuanping Pang, Karl W. K. Tsim, Mingtao Li and Yifan Han. Novel dimeric AChE inhibitor Bis(7)-tacrine, but not Donepezil, prevents glutamate-induced neuronal apoptosis by blocking NMDA receptors. J Biol Chem. 2005, 280(18):18179-88.
7. Xuemin Wang, Xiaoli Tang, Mingtao Li, John Marshall, Zixu Mao. Regulation of neuroprotective activity of myocyte enhancer factor 2 by cAMP-PKA signaling pathway in neuronal survival. J Biol Chem. 2005, 280(17):16705-13.
8. Marcus Wiedmann, Xuemin Wang, X.iaoli Tang, Mingtao Li, Zixu Mao. PI3K/Akt-dependent regulation of the transcription factor myocyte enhancer factor-2 in insulin-like growth factor-1- and membrane depolarization-mediated survival of cerebellar granule neurons. J Neurosci Res. 2005 2005 81(2):226-234.
9. Mingtao Li，Xiaomin Wang，Mary Kay Meintzer，Tracey Laessig，Morris J. Birnbaum and Kim A. Heidenreich. Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3β. Mol Cell Biol. 2000, 20（24）：9356-9363.
10. Mingtao Li，Daniel A. Linsenman，Melissa P.Allen，Mary Kay Meintzer， Xiaomin Wang，Tracey Laessig，Margaret E. Wierman & Kim A. Heidenreich. MEF2A and MEF2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. J. Neurosci. 2001; 21(17):6544-6552.
11. Daniel A. Linseman, Christopher M. Bartley, Shoshona S. Le, Tracey A. Laessig, Ron J. Bouchard, Mary Kay Meintzer, Mingtao Li and Kim A. Heidenreich . Inactivation of the Myocyte Enhancer Factor-2 Repressor Histone Deacetylase-5 by Endogenous Ca2/Calmodulin-dependent Kinase II Promotes Depolarization-mediated Cerebellar Granule Neuron Survival. J Biol Chem 2003, 278:41472–41481.
12. Jing-Ping Yun, Choong-Tsek Liew, Eng Ching Chew, Xiao-Yu Yin, Paul Bo San Lai, Yam Hin Fai, H.K. Richard Li, Mei-Lin Jin, Ming-Xiao Ding, Mingtao Li, Han-Liang Lin, and Wan Yee Lau. Nuclear Matrix Protein Expressions in Hepatocytes of Normal and Cirrhotic Rat Livers Under Normal and Regenerating Conditions. J Cell Biochem. 2004, 91:1269–1279.
13. Hongwei Yang, Xiaodong Hu, Hongmei Zhang, Wenjun Xin, Mingtao Li, Tong Zhang, Lijun Zhou and Xianguo Liu. Roles of CaMKII, PKA, and PKC in the induction and mainternance of LTP of C-fiber-evoked field potentials in rat spinal dorsal horn. J Neurophysiol. 2004, 91: 1122-1133.
14 . Nengwei Hu, Hongmei Zhang, Xiaodong Hu , Mingtao Li, Tong Zhang, Lijun Zhou and Xianguo Liu. Protein Synthesis Inhibition Blocks the Late-Phase LTP of C-Fiber Evoked Field Potentials in Rat Spinal Dorsal Horn. J Neurophysiol, 2003;89:2354- 2359
15 . Juan Sun, Mingtao Li, Jiahuai Han and Jun Gu. Sensitization of differentiated PC12 cells to apoptosis by presenilin-2 is mediated by p38. Biochem. Biophy. Res. Commun., 2001, 287: 536-541.
16. Weibin Cai, Jianfang Ma , Chaoyang Li, Zhonghan Yang, Xia Yang, Wei Liu , Zuguo Liu , Mingtao Li, Guoquan Gao. Enhanced anti-angiogenic effect of a deletion mutant of plasminogen kringle 5 on neovascularization. J Cell Biochem. 2005 Sep 15;(in press).
17. Ming YANG, Cun-you WAGN, Feng ZHOU, Jing TAO, Tao LIU, Hai-yan WEI, Wei LIU, Ming-tao Li, Xian-song FENG. Proteomic Analysis in the Early Process of Pancreatic Regeneration in the Pancreatectomized Rat. Acta Pharmacologica Sinica 2005 (in press)
工 作 條 件
2001年回國，獲得211基金180萬元，組建了一流的分子、細胞生物學實驗室。2002年，作為負責人獲得一期985學科建設經(jīng)費700萬元，籌建了一流的蛋白質組學實驗室并正在主持開展蛋白質科學的前沿性工作。近三年，培養(yǎng)和匯聚了一支從事分子神經(jīng)生物學和蛋白質組學研究的科研隊伍。 這些建設性工作為解決細胞信號轉導、基因調控以及本項目的核心問題奠定了扎實的基礎。
項目負責人黎明濤所在單位——中山大學基礎醫(yī)學院藥理教研室是211項目資助學科和國家重點學科。人才濟濟，科研裝備精良。近三年，藥理教研室獲得學科建設資金3000萬元，已購置大型儀器如質譜儀、激光共聚焦顯微鏡、超速離心機、流式細胞儀、高效液相和蛋白質分離純化系統(tǒng)等。這是申請者視為非常可貴的研究工作環(huán)境。
申請者簡歷
申請者和項目組主要成員
學歷
研究工作簡歷
近期已發(fā)表與本項目有關的文章目錄
獲得學術獎勵情況
在本項目中承擔的任務。
黎明濤 (Li Mingtao)
項目負責人，中山大學基礎醫(yī)學院藥理教研室教授，博士生導師，中山醫(yī)學院蛋白質組學實驗室主任。于1984年、1989年和1996年分別獲得醫(yī)學學士、碩士和博士學位。
主要研究領域是神經(jīng)元凋亡的信號轉導、基因調控和蛋白質組學。在美國Department of Pharmacology, University of Colorado Health Sciences Center從事兩年博士后研究（1999-2001），主攻凋亡的信號轉導、基因調控和蛋白質組學。
近五年發(fā)表了14篇SCI論文，其中：作為第一作者，在國際核心雜志Molecular and Cellular Biology(Impact Factor, 10.03)和 Journal of Neuroscience(IF, 8.4)發(fā)表了具有創(chuàng)新性的文章；作為通訊作者，最近在Neurosci Res(IF, 2.4) 和Neurosci Lett（IF，2.2）等期刊上發(fā)表了開拓性的文章。近五年（1998－2004）作為第一主持人獲得13項基金，包括：4項國家自然科學基金；5項省自然科學基金；3項市基金；1項教育部基金。
發(fā)表的相關論文
1. Leyu Shi , Shoufang Gong, Zhongmin Yuan , Chi Ma, Yanling Liu, Chuanfu Wang , Wenming Li, Rongbiao Pi, Shoujian Huang, Ruzhu Chen , Yifan Han , Zixu Mao, and Mingtao Li(通訊作者). Activity deprivation-dependent induction of the proapoptotic BH3-only protein Bim is independent of JNK/c-Jun activation during apoptosis in cerebellar granule neurons. Neurosci Lett. 2005, 375:7－12.
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皮榮標(Pi Rongbiao)
33歲，博士學位，講師。2002年畢業(yè)于中山大學，獲神經(jīng)藥理學博士。同年赴香港科技大學生物化學系從事博士后研究，現(xiàn)在中山大學藥學院任講師。主要研究興趣涉及神經(jīng)保護藥物的作用及其機制的研究。曾負責或參加包括國家自然科學基金等多項研究。已發(fā)表或待發(fā)表論著近20篇，其中SCI論文5篇。
皮博士與本人合作達11年，有共同的研究趣向，作為共同作者發(fā)表多篇SCI論文。他掌握了本項目涉及的大部分實驗方法和技術，尤其在腺病毒載體構建方面積累了經(jīng)驗（見文章）。主要負責腺病毒載體構建等工作。
發(fā)表的相關論文
1. Rongbiao Pi, Wenming Li, Nelson T.K.Lee, Hugh H.N.Chan, Yongmei Pu, Ling Nga Chan, Nikolaus J. Sucher, Doanld C. Chang, Mingtao Li and Yifan Han. Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem. 2004, 91:1212-1230.
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申請項目同行評議意見反饋信
黎明濤先生：
您好！您申請的項目經(jīng)專家投票表決，同意資助。關于你的項目的同行評議意見如下： 1. 本項目在小腦顆粒細胞撤鉀的離體凋亡模型中，發(fā)現(xiàn)了一種直接調節(jié)Bim的新轉錄因子SP1，申請人試圖采用腺病毒轉染技術、基因突變以及分子生物學方法進一步論證SP1是直接調控bim基因的這一假說。立項具有前言性，申請人工作基礎好，并與美國Emory大學、香港大學有長期的合作條件，完全能夠完成本項課題。建議優(yōu)先資助。 2. 本項課題的立項依據(jù)較為充分，具有一定的學術創(chuàng)新及科學意義。研究內容明確、技術路線清晰、研究方法和方案可行。申請者有較高的學術水平，以及多次主持國家自然科學基金課題的經(jīng)驗。同時，申請者所在單位又有比較好的實驗室及條件。建議給予資助。 3. 課題研究具有較好的工作基礎，研究具有較高的學術價值，建議資助。 4. 同意資助。理由：該項目立論依據(jù)充分，其重要的意義表現(xiàn)在澄清撤鉀誘導神經(jīng)元凋亡時，Bim上調的細胞內信號轉導機制。申請者有較好的研究基礎和研究能力，項目的內容設置合適，重點突出，總體方案合理，技術路線可行，可資助。 5. This is a nicely writen proposal with a clear aim and practical approaches. Further, the group has published results related to the current proposal, indicating the ability of the group to perform the experiments.
獲得資助的決定因素
工作基礎好
學術創(chuàng)新性及學術價值
立項依據(jù)充分
研究內容明確
技術路線清晰
重點突出、方案合理
國際合作
以JNK/CDK5/GSK3β為靶治療PD
JNK Neurosci Res 2004, 48:195-202
Drug News Perspect.2004 17(10):646-54
GSK3β Mingtao Li, et al, unpublished data
CDK5 PNAS USA 2003,100(23):13650-5
發(fā)表文章補充
Wiedmann M, Wang X, Tang X, Han M, Li M, Mao Z. J Neurosci Res. 2005 Jun 1 [Epub ahead of print]
Wang X, Tang X, Li M, Marshall J, Mao Z. J Biol Chem. 2005, 280(17):16705-13.
Li W, Pi R, Chan HH, Fu H, Lee NT, Tsang HW, Pu Y, Chang DC, Li C, Luo J, Xiong K, Li Z, Xue H, Carlier PR, Pang Y, Tsim KW, Li M, Han Y. J Biol Chem. 2005, 280(18):18179-88.
創(chuàng) 新 點
1. 首次證實JNK是治療PD的有效靶點
2. 證實GSK-3β是治療PD的靶點之一
3. 發(fā)現(xiàn)靛玉紅能夠抑制JNK，對PD具有治療作用
4. JNK/CDK5/ GSK-3β為靶治療PD
5. 用一種化合物抑制JNK/CDK5/ GSK-3β
我們對完成此項目充滿信心！
謝 謝！
參 考 文 獻
1. Leyu Shi , Shoufang Gong, Zhongmin Yuan , Chi Ma, Yanling Liu,Chuanfu Wang , Wenming Li, Rongbiao Pi, Shoujian Huang, Ruzhu Chen , Yifan Han , Zixu Mao, and Mingtao Li. Activity deprivation-dependent induction of the proapoptotic BH3-only protein Bim is independent of JNK/c-Jun activation during apoptosis in cerebellar granule neurons. Neurosci Lett. 2005, 375：7－12.
2. Wenya Wang, Leyu Shi, Yuanbin Xie, Chi Ma, Wenming Li, Xingwen Su, Shoujian Huang, Ruzhu Chen, Zhenyu Zhu, Zixu Mao, Yifan Han and Mingtao Li. SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Neurosci Res 2004；48:195-202
實事求是、追求真理的人文精神
Dr. Jonathan Ham以撤NGF的交感神經(jīng)元為模型觀察到JNK/c-Jun[10]和PI3K/Akt/ FKHRL1通路參與Bim的上調[12]，而我們以撤鉀處理CGNs為模型觀察到，這兩條通路不參與Bim的上調。顯然，我們的研究結果不支持Dr. Ham的結論。但是，Dr. Ham讀了我們的文章初稿之后，在提出中肯意見的同時，稱我們的實驗結果非常清楚并對我們的上述結論表示認同(Overall your results are clear and suggest that altering the KCl concentration in CGNs induces the bim promoter by a mechanism that does not involve JNK / c-Jun or FOXO factors)。Dr. Ham這種嚴謹?shù)目茖W態(tài)度令人欽佩，值得學習（尊敬的評審專家，如有必要，本人可以將Dr. Ham的Email原件轉發(fā)給您）。
