李朝军实验室

李朝军，1984进入南京大学生物学系学习至1994毕业，分别获得学士、硕士、博士学位。1996年到1998年于香港科技大学做博士后。1999年6月到2000年5月在美国耶鲁大学医学院做博士后。2001、2002及2004年到美国匹兹堡大学医学院做短期访问。1994-2008年在南京师范大学生生命科学院任教授。2008年调入南京大学工作至今。现任南京大学医学院副院长，南京大学模式动物研究中心教授。中国细胞生物学会副理事长、中国细胞生物学会细胞结构与细胞行为分会副会长，中华医学会医学细胞生物学会理事、中国生物化学与分子生物学会代谢专业委员会委员、江苏省发育生物学会名誉理事长、江苏省动物学会理事。The Journal of Biological Chemistry编委。

实验室从人类疾病的临床现象入手，采取基因组编辑技术建立人类重大疾病小鼠疾病模型，研究疾病相关基因的功能，探明重大疾病发生的分子机制。目前主要研究兴趣是蛋白质的法尼基化修饰与香叶基香叶基化修饰的平衡对细胞物质与能量代谢过程的调控作用，以及对不同器官之间的代谢功能协同维持机体功能稳态的影响。目前的研究发现集中在以下方面：

1.    细胞内不同代谢模式的维持与蛋白质异戊二烯化修饰平衡研究

2.    生殖系统和心血管系统里不同细胞之间的代谢偶联对器官功能的影响

3.    肝脏-肌肉-脂肪之间的代谢协同机制研究

李朝军实验室

研究方向：

机体生物功能稳态的维持－蛋白质的异戊二烯化修饰平衡与细胞代谢稳态

       机体的正常功能依赖于内环境稳态（Homeostasis）的维持，其中细胞内的葡萄糖代谢（糖异生和糖酵解）和脂肪代谢（脂肪酸氧化和脂肪酸合成）对细胞内物质与能量的供应是维持细胞稳态、保持机体内环境稳定的重要条件。葡萄糖和脂肪酸是机体能量的主要来源，不同器官中的细胞、细胞在不同状态下利用葡萄糖和脂肪酸的比例各不相同，且随着器官和细胞的生理和病理状态发生变化。一般情况下，细胞内葡萄糖和脂肪酸等的合成和分解代谢要维持在特定的平衡稳态。一旦稳态失衡，脂代谢和糖代谢紊乱进入恶性循环，将导致多种疾病的发生，如肥胖，糖尿病，高血脂症，及动脉粥样硬化等。我们的科学假设是蛋白质的异戊二烯化修饰的平衡控制了细胞生物功能的平衡，特别是能量代谢的平衡，对机体生物功能稳态的维持至关重要。修饰的平衡的破坏将导致各类疾病的发生。

       蛋白质异戊二烯化是一类广泛存在于各类真核细胞中的蛋白质翻译后修饰，包括以法尼基二磷酸(FPP)为底物的法尼基化修饰(Farnesylation)，和以香叶基香叶基二磷酸(GGPP)为底物的香叶基香叶基化修饰(Geranylgeranylation)。蛋白质异戊二烯化改变了蛋白如小G蛋白的疏水特性，G蛋白异戊二烯化修饰后才能上膜发挥信号分子的调控作用。细胞内的甲羟戊酸途径的分支酶香叶基香叶基二磷酸合酶 (GGPPS) 以15碳的小分子脂肪烃链FPP为底物，催化产生20碳的GGPP分子。我们建立了GGPPS基因在不同小鼠组织的敲除小鼠，改变细胞内的法尼基二磷酸和香叶基香叶基二磷酸（FPP/GGPP）的比值，以及蛋白质法尼基化修饰与香叶基香叶基化修饰的平衡。

      通过研究这些组织器官的表型变化，我们试图阐明蛋白质的法尼基化修饰与香叶基香叶基化修饰的平衡对这些器官物质与能量代谢过程的调控作用，以及不同器官的代谢功能协同对机体功能稳态维持的作用。并以GGPPS为靶点，开发和筛查具有临床应用前景的治疗手段和药物开发的功能分子，将基础医学研究成果转化到临床应用和药物研发中。

       我们发现，Egr-1/GGPPS/MAPK信号可以调控胰岛素信号而提高机体的胰岛素敏感性(EMBO J, 2011; J Biol Chem, 2011; Am J Path, 2011a; AM J Path, 2011b; Am J Path, 2015; J Biol Chem, 2015); GGPPS可以通过影响Rab27a的香叶基化调控胰岛素分泌泡的形成和分泌，进而影响胰岛的功能(J Pathology, 2016)；发现在睾丸支持细胞特异性缺失GGPPS后，可导致炎症被放大并引起小鼠成年不育(J Exp Med, 2013)；在精原细胞中敲除GGPPS引起Rheb的法尼基化激活mTORC1，调控精原干细胞的自我更新和分化的平衡(Sci Rep, 2016)；GGPPS缺失后导致的mTOR的激活还导致心肌细胞过度生长，引起心肌肥大(J Pathology, 2015)；肺上皮细胞中缺失GGPPS通过影响Ras的异戊二烯化调控肺泡的发育(Am J Path, 2016)。另外实验室也关注肝脏再生和肝癌发生机制的研究(J Hep, 2016; FEBS Letter, 2015; BMC Cancer, 2014)。

目前的研究兴趣有：

1.  细胞代谢重编程过程中蛋白质异戊二烯化修饰平衡的调控研究：(李朝军)

2.  肝脏代谢疾病发生发展过程中蛋白质异戊二烯化／磷酸化修饰的调控研究(薛斌)

3.  细胞代谢重编程过程中FPP／GGPP作用蛋白网络的建立与功能研究(方雷)

4.  代谢器官间相互作用过程中蛋白异戊二烯化修饰的作用研究(赵越)

1.    Jia Liu#, Shan Jiang#, Yue Zhao#, et al., Bin Xue*, Chao-Jun Li*. Geranylgeranyl diphosphate synthase(GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions. J Pathol. 2018; 246(3):277-288. (Commentary by Fullerton MD. Does prenylationpredict progression in NAFLD? J Pathol. 2018; Oct 30)

2.    Zhong Chen, et al., Chao-Jun Li*. Geranylgeranyl pyrophosphate synthase facilitates the organization of cardiomyocytes during mid-gestation through modulating protein geranylgeranylation in mouse heart. Cardiovasc Res. 2018;114(7):965-978. (Commentary by Helen M. Phillips. Protein geranygeranylation: a possible new player in congenital heart defects. Cardiovasc Res. 2018;114:922-924)

3.    Jing Wu*, Wei-Wei Tao*, Dan-Yang Chong, Shan-Shan Lai, Chuang Wang, Qi Liu, Tong-Yu Zhang, Bin Xue#, Chao-Jun Li#. Early growth response-1 negative feedback regulates postprandial insulin sensitivity via activating PTP1B expression. FASEB J. 2018, 32(8): 4370-4379

4.    Chen Jiang#, Fan Diao#, et al., Chao-Jun Li*. GGPP-mediated protein geranylgeranylation in oocyte is essential for the establishment of oocyte- granulosa cell communication and primary-secondary follicle transition in mouse ovary. PLoS Genetics, 2017, 13(1): e1006535.

5.    Fan Diao#, Chen Jiang#, Xiu-Xing Wang, Rui-Lou Zhu, Qiang Wang, Bing Yao* , Chao-Jun Li*. Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice. Scientific Reports, 2016, 6:28917|DOI: 10.1038/srep28917

6.    Wen-Jun Jia#, Shan Jiang#, Qiao-Li Tang, Di Shen, Bin Xue, Wen Ning*, Chao-Jun Li*. GGPPS (Geranylgeranyl diphosphate synthase) modulates fetal lung branching morphogenesis possibly through controlling K-Ras prenylation. Am J Pathol, 2016. 186(6):1454-1465

7.    Shan-Shan Lai, Dan-Dan Zhao, Peng Cao, Ke Lu, Ou-Yang Luo, Wei-Bo Chen, Jia Liu, En-Ze Jiang, Zi-Han Yu, Gina Lee, Jing Li, De-Cai Yu, Xiao-Jun Xu, Min-Sheng Zhu, Xiang Gao*, Chao-Jun Li*, Bin Xue* PP2Acα Positively Regulates Mice Liver Regeneration Termination through AKT/GSK3β/Cyclin D1 Pathway. J Hepatology 2016, 64(2):352-360

8.    Shan Jiang*, Di Shen*, Ning Shen, Xiao Han, Bin Xue*, and Chao-Jun Li*. GGPPS mediated Rab27A geranylgeranylation regulates β-cell dysfunction during type 2 diabetes development via affecting insulin granule docked pool formation. J Path, 2016; 238: 109–119.(Commentary by Kowluru A. A lack of "glue" misplaces Rab27A to cause islet dysfunction in diabetes. J Pathol. 2015, doi: 10.1002/path.4671. )

9.    Weiwei Tao, Jing Wu, Qian Zhang, Shan-Shan Lai, Shan Jiang, Chen Jiang, Ying Xu, Bin Xue, Jie Du & Chao-Jun Li.EGR1 regulates hepatic clock gene amplitude by activating Per1 transcription. Scientific Reports, 2015; 5:15212 DOI: 10.1038/srep15212

10.  Weiwei Tao, Jing Wu, Bing-Xian Xie, Yuan-Yuan Zhao, Ning Shen, Shan Jiang, Xiu-Xing Wang, Na Xu, Chen Jiang, Shuai Chen, Xiang Gao, Bin Xue, and Chao-Jun Li. Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway. J Biol. Chem, 2015; 290(33):20086–20097

11.   Na Xu, Shan Guan, Zhong Chen, Yang Yu, Jun Xie, Fei-Yan Pan, Ning-Wei Zhao, Li Liu, Zhong-Zhou Yang, Xiang Gao, Biao Xu, Chao-Jun Li*. The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb/mTORC1 signaling and leads to chronic heart failure. J Pathol. 2015; 235: 672–685. (Cover story)

12.   Ning Shen#, Shan Jiang#, Jia-Ming Lu, Xiao Yu, Shan-Shan Lai, Jing-Zi Zhang, Jin-Long Zhang, Wei-Wei Tao, Xiu-Xing Wang, Na Xu, Bin Xue*, Chao-Jun Li*. The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis. Am J Pathol. 2015, 185(2): 513-523.

13.  Shanshan Lai，Jun Yuan，Dandan Zhao，Ning Shen，Weibo Chen，Yao Ding，Decai Yu, Jing Li, Feiyan Pan, Minsheng Zhu, Chao-Jun Li*, Bin Xue*. Regulation of Mice Liver Regeneration by Early Growth Response-1 through the GGPPS/RAS/MAPK Pathway. Int J Biochem Cell Biol, 2015, 64:147-154.

14.  Wei-Bo Chen, Shan-Shan Lai, De-Cai Yu, Jia Liu, Shan Jiang, Dan-Dan Zhao, Yi-Tao Ding*, Chao-Jun Li*, Bin Xue*. GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis. FEBS Letters 2015, 589(10):1119-1126.

15.  Yu De-Cai, Liu Jia, Chen Jun, Shao Jiao-jiao, Shen Xiao,, Xia Hong-Guang, Li Chao-Jun，Xue, Bin*，Ding, Yi-Tao*. GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis. BMC Cancer, 2014, 14: 248-256.

16.  Dai Gu, Qian Yan, Chen Jie, Meng Fan-Li, Pan Fei-Yan, Shen Wei-Gan, Zhang Sheng-Zhou, Xue Bin, Li Chao-Jun. Calmodulin activation of polo-like kinase 1 is required during mitotic entry, Biochemistry and Cell Biology, 2013, 91(5):287-294.

17.  Tao Weiwei, Shi Jun-Feng, hang Qian, Xue Bin,Sun Yu-Jie, Li Chao-Jun. Egr-1 enhances drug resistance of breast cancer by modulating MDR1 expression in a GGPPS-independent manner. Biomedicine & Pharmacotherapy 2013,67(3):197-202.

18.  Yunxia Zhu, Ai Ma, Hongxiu Zhang, Chaojun Li. PPARc Activation Attenuates Glycated-Serum Induced Pancreatic Beta-Cell Dysfunction through Enhancing Pdx1 and Mafa Protein Stability. PLOS One. 2013.8(2): e56386

19.   Xiu-Xing Wang, Pu Ying, Fan Diao, Qiang Wang, Dan Ye, Chen Jiang, Ning Shen, Na Xu, Wei-Bo Chen, Shan-Shan Lai, Shan Jiang, Xiao-Li Miao, Jin Feng, Wei-Wei Tao, Bing Yao, Zhi-Peng Xu, Hai-Xiang Sun, Jian-Min Li, Jia-Hao Sha, Xing-Xu Huang, Bin Xue, Hong Tang, Xiang Gao, Chao-Jun Li. The protein prenylation alteration in Sertoli cells is associated with adult infertility resulted from childhood Mumps infection. J Exp Med. 2013, 210(8):1559-1574.

20.   Ning Shen#, Yue Shao#, Long Qiao, Run-Lin Yang, Bin Xue, Fei-Yan Pan, Hua-Qun Chen*, Chao-Jun Li*. GGPPS, a new egr-1 target gene, reactivates erk1/2 signaling through increasing ras prenylation. Am J Pathol., 2011,179(6):2740-2750. 

21.   Xiao Yu#, Ning Shen#, Ming-Liang Zhang Fei-Yan Pan, Chen Wang, Wei-Ping Jia, Chang Liu, Qian Gao, Xiang Gao, Bin Xue*, Chao-Jun Li*. Egr-1 enhances insulin resistance by tilting the balance of PI3K/Akt and MAPK signaling in mice. The EMBO J., 2011, 30(18):3754-3765

22.   Ning Shen#, Xiao Yu#, Fei-Yan Pan, Xiang Gao, Bin Xue*, Chao-Jun Li*. An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism. J Biol Chem., 2011, 286(16):14508-15.

23.   Ning Shen, Tao Gong, Jian-Dong Wang, Fan-Li Meng, Long Qiao, Run-Lin Yang, Bin Xue, Fei-Yan Pan, Xiao-Jun Zhou Hua-Qun Chen, Wen Ning*, Chao-Jun Li*. Cigarette-smoke induced pulmonary inflammatory responses are mediated by egr-1/ggpps/mapk signaling.  Am J Pathol., 2011, 178(1):111–119.