个人简介

吴政，复旦大学博士，宾夕法尼亚州立大学博士后，曾担任宾夕法尼亚州立大学研究型助理教授。2020年9月全职加入暨南大学粤港澳中枢神经再生研究院大脑修复中心，担任研究员，长期致力于中枢神经系统疾病的发病机制和干预治疗研究，特别关注GABA能神经传导失调在相关疾病发病过程中的神经机制，包括癫痫（兴奋-抑制失衡与再平衡）、亨廷顿舞蹈症（GABA能神经元丢失与再生）和阿尔茨海默症（胶质细胞释放GABA及其影响）。先后在Nature Communications，Molecular Neurodegeneration和Cell Stem Cell等杂志上发表20余篇具有国际影响力的研究论文，Google学术显示总引用次数超过2200余次，个人H指数15。常年担任Molecular Neurodegeneration和Molecular Neurobiology等杂志的同行审稿人。迄今，以共同发明人的身份已经获得 9 项国际发明专利，其中一项有关亨廷顿舞蹈症的神经再生基因治疗专利，已经与基因治疗公司 Spark therapeutics 签署了战略合作协议，推动临床转化研究。获广东省自然科学基金面上，“珠江人才计划”青年拔尖，“珠江人才计划”创新创业团队，广州市重点研发计划等项目资助。

研究兴趣

1.     GABA传导系统异常在阿尔茨海默症发病过程中的作用机制

γ-氨基丁酸（GABA）是中枢神经系统中主要的抑制性神经递质，对控制维持中枢神经系统的兴奋-抑制平衡至关重要，GABA的功能性失调会导致诸如癫痫，睡眠障碍，自闭症和精神分裂症等多种中枢系统疾病。此外，我们最新的研究还发现，GABA与阿尔茨海默症（Alzheimer’s disease, AD）也密切相关。我们首次发现了在AD模型小鼠大脑中的应激性星型胶质细胞，也可以释放GABA，从而导致大脑过度抑制，影响AD小鼠海马区LTP的诱导和学习记忆。小分子特异性地抑制胶质细胞GABA的释放（Nature Communications，2014）或GABA合成酶基因的单倍体不足（Molecular Neurodegeneration， 2017），都可以显著性的改善AD的症状，增强学习记忆。未来，我们将继续深入研究应激性星形胶质细胞释放的GABA对不同脑区和不同类型神经元活性及神经网络活动的影响，揭示其导致认知障碍的神经机制，并研发相应的干预治疗策略，进而达到改善AD模型小鼠的认知能力，为老年痴呆症的干预治疗提供新的思路。

2.     原位神经再生基因治疗的基础开发和优化

人类大脑约有860亿神经元，同时也有数量相当的胶质细胞。神经元缺乏再生能力，胶质细胞则能通过分裂而再生。中枢损伤或病变通常伴随着神经元的不可逆丢失，同时还常有胶质细胞的异常增生。基于这些病理特征，我们提出是否可以通过细胞重编程技术，进而将增生的胶质细胞改造成为功能性的神经元，从而达到神经再生的目的，为神经再生这一世界性的医学难题提供新思路。目前，我们的研究已经证实可以在老年痴呆症（Cell Stem Cell，2014）、亨廷顿舞蹈症（Nature Communications，2020）和脑卒中（Molecular Therapy, 2020）小鼠大脑中，将胶质细胞原位转化为功能性的神经元，并取得了显著的治疗效果。目前，我们正在优化在体细胞重编程技术，提高胶质细胞转化为神经元的效率，扩大胶质细胞转化为神经元的脑区范围，定向再生特定亚型的神经元（如GABA能神经元， Nature Communications，2020），以及减少重编程基因递送策略的毒副作用等，开发实用性的原位神经再生基因治疗，造福广大患者。

论文列表

(1).Xiaosong He, Xin Wang, Hui Wang, Tao Wang, Fuhan Yang, Yuchen Chen, Zifei Pei, Yuting Bai, Wen Li, Zheng Wu, Gong Chen. Neurod1 regulated endothelial gene expression to modulate transduction of AAV-PHP.eB and recovery progress after ischemic stroke. Aging Dis, 2023, 14:6.

(2).Yaowei Guo, Junliang Chen, Wenyu Ji, Liang Xu, Yu Xie, Shu He, Chuying Lai, Kaiyu Hou, Zeru Li, Gong Chen*, Zheng Wu*. High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain. Mol Ther-Meth Clin D, 2023, 31: 1011102. (首要通讯作者)

(3). Hui Wang, Liang Xu, Chuying Lai, Kaiyu Hou, Junliang Chen, Yaowei Guo, Abhijeet Sambangi, Shreya Swaminathan, Chunming Xie*, Zheng Wu*, Gong Chen*. (2021) Region-specific distribution of Olig2-expressing astrocytes in adult mouse brain and spinal cord. Molecular Brain. 2021 Feb 17;14(1):36. (并列通讯作者)

(4). Zheng Wu, Matthew Parry, Xiao-Yi Hou, Min-Hui Liu, Hui Wang, Rachel Cain, Zi-Fei Pei, Yu-Chen Chen, Zi-Yuan Guo, Sambangi Abhijeet, Gong Chen. （2020）Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease. Nature Communications. Feb 27, 2020.（唯一第一作者）

(5). Yu-Chen Chen, Ning-Xin Ma, Zi-Fei Pei, Zheng Wu, Fabricio H Do-Monte, Susan Keefe, Emma Yellin, Miranda S Chen, Jiu-Chao Yin, Grace Lee, Angélica Minier-Toribio, Yi Hu, Yu-Ting Bai, Kathryn Lee, Gregory J Quirk, Gong Chen. (2020) A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion. Molecular Therapy. Jan 8, 2020.

(6). Zheng Wu*, QW Huo*, L Ren, FP Dong, MY Feng, Y Wang, YT Bai, B Lüscher, ST Li, GL Wang, C Long, Y Wang, G Chen. (2019) Gluconate suppresses seizure activity in developing brains by inhibiting CLC-3 chloride channels. Molecular Brain. 2019, 15; 12(1):50. (并列第一作者)

(7). DY Jiang, Zheng Wu, CT Forsyth, Y Hu, SP Yee, G Chen. (2018) GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Molecular Brain. 2018, 11 (1), 31.

(8). Y Wang, Zheng Wu*, YT Bai, GY Wu*, G Chen*. (2017) Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease. Molecular Neurodegeneration. 2017, 12:73. (并列通讯作者).

(9). L Chen, L Wan, Zheng Wu, W Ren, Y Huang, B Qian, Y Wang. (2017) KCC2 downregulation facilitates epileptic seizures. Scientific Reports. Dec; 7(1):156.

(10). Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Zheng, Carromeu C, Muotri AR, Marchetto MC, Gage FH, Chen G. (2016) KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci U S A.  Jan 19; 113(3):751-6.

(11). Zheng Wu, Alan C. Foster, Ursula Staubli, Xia Wu, Chicheng Sun, Xin Tang, Yong-Xin Li, Gong Chen. (2015) Effects of 3-aminoglutarate, a “silent” false transmitter for glutamate neurons, on synaptic transmission and epileptiform activity. Neuropharmacology. Oct; 97:95-103.（唯一第一作者）

(12). Zheng Wu, Ziyuan Guo, Marla Gearing, Gong Chen. (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nature Communications. June 13, 2014.（唯一第一作者）

(13). Wan L, Liu X, Wu Zheng, Ren W, Kong S, Dargham RA, Cheng L, Wang Y. (2014) Activation of extrasynaptic GABA(A) receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons. Neurosci Bull.  Oct; 30(5):866-76.

(14). Guo Z, Zhang L, Wu Zheng, Chen Y, Wang F, Chen G. (2014) In Vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s Disease model. Cell Stem Cell. 14(2):188-202.

(15). Wu X*, Huang L*, Wu Zheng, Zhang C, Jiang D, Bai Y, Wang Y, Chen G. (2013) Homeostatic competition between phasic and tonic inhibition. J Biol Chem. 288(35):25053-65.

(16). Yajie Sun*, Zheng Wu*, Shuzhen Kong, Dongyun Jiang, Anar Pitre, Yun Wang, and Gong Chen. (2013) Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors. Mol Brain. 6:21. (并列第一作者)

(17). Wu X, Wu Zheng, Ning G, Guo Y, Ali R, Macdonald RL, De Blas AL, Luscher B, Chen G. (2012) gamma-Aminobutyric Acid Type A (GABAA) Receptor Alpha Subunits Play a Direct Role in Synaptic versus Extrasynaptic Targeting. J Biol Chem. 287(33): 27417-27430.

(18). Qian B, Sun Y, Wu Zheng, Wan L, Chen L, Kong S, Zhang B, Zhang F, Wang ZY, Wang Y. (2011) Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetized rats. Seizure. 20(4):312-9.

(19). Chen CR, Tan R, Qu WM, Wu Zheng, Wang Y, Urade Y, Huang ZL. (2011) Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, exerts anti-epileptic effects via GABA-benzodiazepine receptor complex in mice, British Journal of Pharmacology. 164(5):1534-46.

(20). Zheng Wu*, Qi Xu*, Liecheng Wang, et al. (2009) Protective effect of resveratrol against kainate-induced temporal lobe epilepsy in rats. Neurochemical Research. 34(8):1393–1400. (并列第一作者)

(21). Zheng Wu, Qi Xu, Ruo Bing Qian, Feng Yu, Lian Yu, DH Kong, Liecheng Wang. Temporal lobe epilepsy animal model established by stereotaxic microinjection of kainic acid. Neural Regen Res, 2008, 3: 436-440. (唯一第一作者)