2015-now Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Principal Investigator and Lab Head, Shanghai, China
2009-2015 Genentech Inc. (Roche Group), Postdoctoral Research Fellow, California, USA
2008-2009 Massachusetts Institute of Technology, Postdoctoral fellow, Massachusetts, USA
2002-2007 Vanderbilt University, Ph.D. (Neuroscience), Tennessee, USA
2001-2002 Singapore-MIT Alliance, M.S. (Molecular Engineering in Biological and Chemical Systems), Singapore
1997-2001 Beijing University, B.S. (Biochemistry and Molecular Biology), Beijing, China

2015至今 中国科学院生物与化学交叉研究中心 研究员，课题组长
2009-2015 Genentech制药公司（罗氏集团）博士后研究员
2008-2009 麻省理工学院(MIT)Picower学习与记忆研究中心 博士后
2002-2007 范德比尔特大学(Vanderbilt University)神经药物开发中心 博士
2001-2002 新加坡和麻省理工学院联合项目生物与化学分子系统工程 硕士
1997-2001 北京大学生命科学学院生物化学及分子生物学系 学士

Research interests of Chen lab:

Neurons communicate with others through chemical synapses. This process is called synaptic transmission, which underlies many essential brain functions. Glutamate is the major excitatory neurotransmitter mediating excitatory synaptic transmission. But how glutamatergic synaptic transmission impacts brain functions and how its abnormalities contribute to brain diseases remain unclear. Using an interdisciplinary research approach including neuroscience and chemical biology, Synapses and Brain Diseases Group focuses on two related fields: 1. How NMDA type of glutamate receptors control brain function at molecular, cellular and circuit levels? 2. How synapses are damaged in neurodegenerative diseases, particularly in Alzheimer’s disease?

In specific, NMDA receptors (NMDAR) are glutamate-gated ionic channels involved in a broad spectrum of brain disorders, including psychiatric diseases, brain injury and neurodegenerative diseases, etc. But how NMDAR dysfunction contributes to these diseases remains unclear. We are probing these questions from three angles: 1. How NMDAR signaling regulates glial cell? 2. How NMDAR circuits control animal behavior? 3. In collaborating with medicinal chemists, we are also searching for novel compounds as tools to study NMDAR function or for better therapeutic applications.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting a huge population worldwide. Currently, there is no disease-modifying therapies available. Many evidence (particularly from human genetic studies) support that excessive Aβ is the cause of AD pathogenesis. However, the Aβ-targeting therapies have only provided limited benefits in clinical trials up to date. One possibility is that there are caveats in the current Aβ hypothesis. We are re-visiting the key molecules in Aβ cascade or associated with AD risks, including APP, BACE1, ApoE and TDP-43. Particularly, we are interested in how dysfunction of these molecules leads to synaptic degeneration, a damage many years preceding the ultimate massive neuronal death in AD progress. Our goal is to define novel mechanisms explaining AD pathogenesis and identify better drug targets for earlier interventions.

突触与脑疾病课题组研究方向：

神经细胞通过化学突触相互沟通。该过程就是突触传递，是脑功能的基础。谷氨酸是最主要介导兴奋性突触传递的神经递质。但是谷氨酸传递系统如何影响脑功能及其在脑疾病中的角色不明。突触与脑疾病课题组使用神经生物学和化学生物学为核心的交叉研究手段聚焦两个相关的研究方向：1.NMDA型谷氨酸受体如何在分子、细胞和环路水平调控脑功能？2.阿尔兹海默症中突触退化的分子机制。

其中NMDA型谷氨酸受体是谷氨酸门控的离子通道，其功能异常是多种脑疾病的致病原因，包括精神类疾病、脑损伤和神经退行性疾病等。但是NMDA受体究竟是如何导致这些疾病的，机制并不清楚。本课题组主要从三个方面对此进行研究：1.NMDA受体如何调控胶质细胞功能？2.NMDA环路功能。3.开发针对NMDA受体的新型药物用于基础研究和新的治疗手段。

阿尔兹海默症（AD）是最常见的神经退行性疾病，目前完全没有可以改变AD疾病进程的治疗手段。大量证据（尤其是人类遗传学证据）支持过量生成的Aβ是导致AD的原因。可惜的是，针对Aβ的治疗手段目前均以失败告终。提示Aβ假说尚有不足之处。本课题组正在重新分析Aβ相关蛋白以及AD风险因子的功能对突触的调控，其中包括APP, BACE1, ApoE and TDP-43。突触丢失是AD初期的退行性病变，远早于后期神经元的大量死亡，可能是更好的干预节点。因此，我们对于这些AD风险蛋白如何导致突触退行性病变尤其感兴趣。我们的目标是寻找新的AD致病机制以及药物干预靶点。

1. Hou X., Zhang X., Zou H., Guan M., Fu C., Wang W., Zhang Z., Geng Y., Chen Y. (2023) Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3 and ApoE4. Neuron 111: 1-16

2. Ni J., Ren Y., Su T., Zhou J., Fu C., Lu Y., Li D., Zhao J., Li Y., Zhang Y., Fang Y., Liu N., Geng Y., Chen Y. (2023) Loss of TDP-43 function underlies hippocampal and cortical synaptic deficits in TDP-43 proteinopathies. Mol. Psychiatry 28(2):931-945. (Cover)

3. Zhou J., Geng Y., Su T., Wang Q., Ren Y., Zhao J., Fu C., Weber M., Lin H., Kaminker., Liu N., Sheng M., Chen Y. (2022) NMDA receptor-dependent Prostaglandin-Endoperoxide Synthase 2 induction in neurons promotes glial proliferation during brain development and injury. Cell Rep. 38(13):110557

4. Chen Y., Wang Y., Ertürk A., Kallop D., Jiang Z., Weimer R.M., Kaminker J., Sheng M. (2014) Activity-induced Nr4a1 regulates spine density and distribution pattern of excitatory synapses in pyramidal neurons. Neuron. 83:431-43. (Recommended by F1000)

5. Chen Y., Wang Y., Sheng M. and Kaminker J. (2014) Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for Histone Deacetylase 4. J Neurosci. 34:15327-39.

6. Ayala, J.E. *, Chen Y.*, Banko J.L., Sheffler D., Williams R., Telk A.N., Watson N.L., Xiang Z., Zhang Y., Jones P.J., Lindsley C.W., Olive M.F. and Conn P.J. (2009) mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology. 34:2057-71. (* contributed equally)

7. Chen Y., Goudet C., Pin J.P. and Conn P.J. (2008) CPPHA acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol. 73:909-18

8. Chen Y., Nong Y., Goudet C., Hemstapat K., de Paulis T., Pin J.P. and Conn J.P. (2007) Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol Pharmacol. 71:1389-98