陈哲宇
长期致力于神经营养因子与神经精神疾病关系的研究
个性化签名
- 姓名:陈哲宇
- 目前身份:
- 担任导师情况:
- 学位:
-
学术头衔:
博士生导师, 国家杰出青年科学基金获得者, 教育部“新世纪优秀人才支持计划”入选者
- 职称:-
-
学科领域:
神经生物学
- 研究兴趣:长期致力于神经营养因子与神经精神疾病关系的研究
陈哲宇,男,山东大学医学院教授,1974年2月出生,浙江省湖州人,1990年9月参加工作,2000年6月获医学博士学位。曾任第二军医大学学员、神经生物学教研室讲师,美国匹兹堡大学医学院神经生物系博士后,美国康乃尔大学医学院博士后、讲师、助理教授。陈哲宇教授长期致力于神经营养因子与神经精神疾病关系的研究,从分子细胞水平到整体动物水平寻找抑郁症等精神疾病发生的基因及环境因素,并探讨可能的干预措施。陈哲宇教授已承担国家杰出青年科学基金、自然科学基金、高等学校科技创新工程培育项目等多项科研项目,相关科研成果在《科学》、《神经科学杂志》等国际知名杂志上发表,总计达30余篇,合计影响因子100多分,并被引用300余次。陈哲宇教授曾先后获得全国百篇优秀博士学位论文奖、军队科技进步二等奖,被评选为上海市青年科技启明星、NARSAD Young Investigator Award、教育部新世纪优秀人才、山东省十一届“青年五四奖章标兵”,并获聘山东省“泰山学者”特聘教授。
-
主页访问
1722
-
关注数
0
-
成果阅读
527
-
成果数
12
陈哲宇, Zhe-Yu Chen, *†, Alessandro Ieraci, *, Michael Tanowitz, ‡ and Francis S. Lee*§
Vol. 16, 5761-5772, December 2005,-0001,():
-1年11月30日
Endocytic trafficking of signaling receptors to alternate intracellular pathways has been shown to lead to diverse biological consequences. In this study, we report that two neurotrophin receptors (tropomyosin-related kinase TrkA and TrkB) traverse divergent endocytic pathways after binding to their respective ligands (nerve growth factor and brainderived neurotrophic factor). We provide evidence that TrkA receptors in neurosecretory cells and neurons predominantly recycle back to the cell surface in a ligand-dependent manner. We have identified a specific sequence in the TrkA juxtamembrane region, which is distinct from that in TrkB receptors, and is both necessary and sufficient for rapid recycling of internalized receptors. Conversely, TrkB receptors are predominantly sorted to the degradative pathway. Transplantation of the TrkA recycling sequence into TrkB receptors reroutes the TrkB receptor to the re cycling pathway. Finally, we link these divergent trafficking pathways to alternate biological responses. On prolonged neurotrophin treatment, TrkA receptors produce prolonged activation of phosphatidylinositol 3-kinase/Akt signaling as well as survival responses, compared with TrkB receptors. These results indicate that TrkA receptors, which predominantly recycle in signal-dependent manner, have unique biological properties dictated by its specific endocytic trafficking itinerary.
-
58浏览
-
0点赞
-
0收藏
-
0分享
-
77下载
-
0评论
-
引用
【期刊论文】ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin
陈哲宇, Henry K. Teng, , Kenneth K. Teng, Ramee Lee, Saundrene Wright, Seema Tevar, Ramiro D. Almeida, Pouneh Kermani, Risa Torkin, Zhe-Yu Chen, Francis S. Lee, Rosemary T. Kraemer, Anders Nykjaer, and Barbara L. Hempstead
The Journal of Neuroscience, June 1, 2005, 25 (22): 5455-5463,-0001,():
-1年11月30日
Brain-derived neurotrophic factor (BDNF) is best characterized for critical roles in neuronal survival, differentiation, and synaptic modulation mediated by the TrkB receptor tyrosine kinase. Developmentally regulated death signaling by BDNF has also been demonstrated via activation of p75NTR. Because recent studies suggest that proNGF, the precursor form of NGF, is more active than mature NGF in inducing apoptosis after binding to p75NTR and a coreceptor, sortilin, we asked whether the precursor of BDNF (proBDNF) is also a proapoptotic ligand in the nervous system. proBDNF is secreted by cultured neurons, and recombinant proBDNF binds to sortilin. In sympathetic neurons coexpressing sortilin and p75NTR, we found that proBDNF is an apoptotic ligand that induces death at subnanomolar concentrations. In contrast, mature BDNF, but not proBDNF, is effective in inducing TrkB phosphorylation. proBDNF effects are dependent on cellular coexpression of both p75NTR and sortilin, because neurons deficient in p75NTR are resistant to proBDNF-induced apoptosis, and competitive antagonists of sortilin block sympathetic neuron death. Moreover, addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells coexpressing both sortilin and p75NTR, suggesting that interaction of proBDNF with both receptors on the cell surface is required to initiate cell death. Together with our past findings, these data suggest that the neurotrophin family is capable of modulating diverse biological processes via differential processing of the proneurotrophins.
proBDNF, apoptosis, p75 receptor, sortilin, neuron, neurotrophin
-
45浏览
-
0点赞
-
0收藏
-
0分享
-
181下载
-
0评论
-
引用
陈哲宇, Zhe-Yu Chen, , Alessandro Ieraci, Henry Teng, Henning Dall, Chui-Xiang Meng, Daniel G. Herrera, Anders Nykjaer, Barbara L. Hempstead, and Francis S. Lee
The Journal of Neuroscience, June 29, 2005, 25 (26): 6156-6166,-0001,():
-1年11月30日
Brain-derived neurotrophic factor (BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the human bdnf gene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses.
brain-derived neurotrophic factor, polymorphism, prodomain, sortilin, intracellular trafficking, regulated secretion
-
49浏览
-
0点赞
-
0收藏
-
0分享
-
82下载
-
0评论
-
引用
陈哲宇, Rithwick Rajagopal, Zhe-Yu Chen, Francis S. Lee, and Moses V. Chao
The Journal of Neuroscience, July 28, 2004, 24 (30): 6650-6658,-0001,():
-1年11月30日
Neurotrophins, such as NGF and BDNF, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and intracellular signaling. It has been shown that activation of Trk receptor tyrosine kinases can also occur via a G-protein-coupled receptor (GPCR) mechanism, without involvement of neurotrophins. Two GPCR ligands, adenosine and pituitary adenylate cyclase-activating polypeptide (PACAP), can activate Trk receptor activity to increase the survival of neural cells through stimulation of Akt activity. To investigate the mechanism of Trk receptor transactivation, we have examined the localization of Trk receptors in PC12 cells and primary neurons after treatment with adenosine agonists and PACAP. In contrast to neurotrophin treatment, Trk receptors were sensitive to transcriptional and translational inhibitors, and they were found predominantly in intracellular locations particularly associated with Golgi membranes. Biotinylation and immunostaining experiments confirm that most of the transactivated Trk receptors are found in intracellular membranes. These results indicate that there are alternative modes of activating Trk receptor tyrosine kinases in the absence of neurotrophin binding at the cell surface and that receptor signaling may occur and persist inside of neuronal cells.
NGF, tyrosine phosphorylation, basal forebrain, adenosine, PACAP, Golgi apparatus
-
39浏览
-
0点赞
-
0收藏
-
0分享
-
68下载
-
0评论
-
引用
【期刊论文】Olfactory ensheathing cells genetically modi
陈哲宇, Li Cao, Li Liu, , Zhe-Yu Chen, Li-Mei Wang, Jun-Li Ye, Hai-Yan Qiu, Chang-Lin Lu, and and Cheng He
Brain (2004), 127, 535-549,-0001,():
-1年11月30日
Olfactory ensheathing cell (OEC) transplantation has emerged as a very promising therapy for spinal cord repair. In this study, we tested the ability of genetically modi
spinal cord injury, olfactory ensheathing cell, glial cell line-derived neurotrophic factor, transplantation, gene therapy
-
44浏览
-
0点赞
-
0收藏
-
0分享
-
68下载
-
0评论
-
引用
陈哲宇, Li-Mei Wang#, Qing Zhang#, Qi Zhang, Wei Zhu, Cheng He, Chang-Lin Lu, Da-Fu Ding* and Zhe-Yu Chen*
JBC Papers in Press. Published on October 16, 2003 as Manuscript M306287200,-0001,():
-1年11月30日
Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 (GFRα1), and receptor protein tyrosine kinase, Ret. While structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFRα1 function. In this study, based on evolutionary trace method and residues relative solvent accessibility prediction, a set of trace residues which are solvent accessible were selected for site-directed mutagenesis. A series of GFRα1 mutations were made and PC12 cell lines stably expressing different GFRα1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNFGFRα1Ret interaction assay, residues N152N153, R259 and S316N317S318 in the GFRα1 central region were found to be critical for GFRα1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in GFRα1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152AN153A or S316AN317AS318A mutation in the GFRα1 molecule still retained the ability to bind with Ret. Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 (GFRα1), and receptor protein tyrosine kinase, Ret. While structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFRα1 function. In this study, based on evolutionary trace method and residues relative solvent accessibility prediction, a set of trace residues which are solvent accessible were selected for site-directed mutagenesis. A series of GFRα1 mutations were made and PC12 cell lines stably expressing different GFRα1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNFGFRα1Ret interaction assay, residues N152N153, R259 and S316N317S318 in the GFRα1 central region were found to be critical for GFRα1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in GFRα1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152AN153A or S316AN317AS318A mutation in the GFRα1 molecule still retained the ability to bind with Ret.
-
52浏览
-
0点赞
-
0收藏
-
0分享
-
27下载
-
0评论
-
引用
陈哲宇, Z.-Y. CHEN, a*, Y.-F. CHAI, a, b, L. CAO, A.-J. HUANG, R.-Y. CUI, C.-L. LUa and C. HEa
Neuroscience Vol. 104, No.2, pp. 593-598, 2001,-0001,():
-1年11月30日
glial cell line-derived neurotrophic factor,, glial cell line-derived neurotrophic factor receptor a1,, mitogen-activated protein kinase,, phosphatidylinositol 3-kinase,, survival,, differentiation.,
-
45浏览
-
0点赞
-
0收藏
-
0分享
-
28下载
-
0评论
-
引用
陈哲宇, Zhe-Yu Chen*, Yan-Feng Chai, Li Cao, Chang-Lin Lu, Cheng He*
Brain Research 902(2001)272-276,-0001,():
-1年11月30日
Adult rat sciatic nerve was transected and sutured with an entubulation technique. The nerve interstump gap was filled with either collagen gel (COL) or collagen gel mixed with glial cell line-derived neurotrophic factor (COL/GDNF). Four weeks after nerve transection, horseradish peroxidase (HRP)-labelled spinal cord motoneurons and the myelinated distal stump axons were quantified. Compared with the COL group, the percentages of labeled spinal somas and axon number were significantly increased after topically applied glial cell line-derived neurotrophic factor (GDNF). The functional recovery of the transected nerve was improved in COL/GDNF group. GAP-43 expression was also significantly higher in COL/GDNF group 1 and 2 weeks after sciatic nerve axotomy vs. COL group. These data provide strong evidence that GDNF could promote axonal regeneration in adult rats, suggesting the potential use of GDNF in therapeutic approaches to peripheral nerve injury and neuropathies.
Sciatic nerve, Axonal regeneration, GDNF, GAP-43
-
44浏览
-
0点赞
-
0收藏
-
0分享
-
35下载
-
0评论
-
引用
【期刊论文】Human Glial Cell-Line-Derived Neurotrophic Factor: A Structure-Function Analysis
陈哲宇, Zhe-Yu Chen, *, Zhi-Yong He, †, Cheng He, Chang-Lin Lu, * and Xiang-Fu Wu†
Biochemical and Biophysical Research Communications 268, 692-696 (2000),-0001,():
-1年11月30日
Glial cell-line-derived neurotrophic factor (GDNF) is a protein known to enhance the survival of dopaminergic and motor neurons. It has been shown to have therapeutic potential in the treatment of Parkinson’s disease and other neurodegenerative diseases. GDNF gene was modified by deletion and insertion mutagenesis using PCR methods. The various mutants were all highly expressed in Escherichia coli. The recombinant proteins were purified and their survival-promoting activities were determined by motor neurons. The result showed that the C-terminus was critical for structure stability of GDNF, and the a-helix, finger1 and finger2 regions were involved in receptor binding, while the N-terminus was not essential for the biological functions of GDNF.
-
42浏览
-
0点赞
-
0收藏
-
0分享
-
65下载
-
0评论
-
引用
陈哲宇, Zhe-Yu Chen, *, Jian-Xin Sun, †, Jian-Hong Li, Cheng He, , Chang-Lin Lu, * and Xiang-Fu Wu†
Biochemical and Biophysical Research Communications 273, 902-906 (2000),-0001,():
-1年11月30日
Recombinant human glial cell line-derived neurotrophic factor (GDNF) has been expressed at high levels and produced in large quantities in baculovirusinfected Trichoplusia ni cells (Tn-5B1-4). The glycosylated protein was purified using immunoaffinity chromatography and gel filtration. Pure, recombinant human GDNF promoted the survival and morphological differentiation of embryonic dopaminergic neurons and enhanced axonal regeneration after sciatic nerve transection. Because recombinant bioactive human GDNF can be obtained in large quantities, and purified to near homogeneity, they are suitable for evaluation in animal models.
GDNF, baculovirus, purification, dopaminergic neuron, regeneration.,
-
46浏览
-
0点赞
-
0收藏
-
0分享
-
65下载
-
0评论
-
引用