Research Interests:
1. GPCR-related Drug Discovery and Mechanism Study
2. Induced Pluripotent Stem cell – A Chemical Biology Approach
Research Description:
1. GPCR-related Drug Discovery and Mechanism Study
G-protein-coupled receptors (GPCR) constitute one of the largest and most versatile families of cell surface receptors. GPCR are 7 transmembrane proteins with the amino terminal and carboxy terminal located in the extracellular and intracellular spaces, respectively. GPCR recognize and respond to a variety of extracellular stimulants and endogenous ligands, including light, odors, taste substances, hormones, chemotactic factors, and neurotransmitters. Due to the variety of physiological and pathological functions regulated by GPCR, they were considered the most promising drug targets in the pharmaceutical industry. It is estimated that over 40% of the marketed drugs are modulators of GPCR functions. With the completion of the Human Genome Project, approximately 1000 genes encoding GPCR were identified, but only about 200 have known ligands and functions. Searching for ligands of the orphan GPCR and better modulators of known receptors will provide new opportunities in future drug discovery. Our research on GPCR is mainly focused on the following aspects:
(1)GPCR signal transduction and Autoimmune Diseases. We use mouse EAE model to study the autoimmune disease Multiple Sclerosis. We discovered several new GPCR that are involved in the induction of EAE. We are using genetic and pharmacological approaches to verify the relationship between these GPCR and EAE, in hope to find new therapeutic targets for autoimmune diseases.
(2)GPCR signal transduction and Alzheimer’s Diseases. Previous studies indicated that the activation of certain GPCR, such as beta-2 adrenergic receptor, might contribute to Abeta accumulation in Alzheimer disease. With cell based Abeta generation model and transgenic mice models, we are searching for new GPCR that may play a role in AD pathogenesis.
(3)High-throughput and high-content assay development for GPCR-based drug discovery. Our GPCR screening platform includes >60 GPCR stable cell lines that can readily be used for HTS/HCS and the list is still growing. Our latest targets include: CCR6, GPR40, GPR119, GPR120, and etc.
2. Induced Pluripotent Stem cell – A Chemical Biology Approach
Induced Pluripotent Stem cells (iPSC) can be generated from differentiated cells via reprogramming initiated by defined transcriptional factors. Mouse iPSCs are similar to ESCs in most aspects and can develop into individuals after tetraploid complementation. The iPSC technology has attracted enormous interests due to its potential biomedical applications. Patient-specific iPSCs could be created and they could be further differentiated into functional autologous cells for cell-based therapy without immuno-compatibility issues and ethical concerns.
However, iPSCs applications are hindered by low induction efficiency and safety concerns due to the use of oncogenes and incorporation of viral DNA sequences. Our research is focused on searching small molecules that can enhance the generation of iPSCs or compensate the requirement of certain oncogenic factors. These chemicals can not only improve the reprogramming efficiency, but also help to dissect the underlying mechanisms of reprogramming.
Key Word: GPCR, Drug Discovery, Autoimmune Diseases, Multiple Sclerosis, Alzheimer’s Disease, High-throughput Screening, Induced Pluripotent Stem cells, Chemical Biology
Representative Publication (less than 20 papers)：
（1）Xiaoyuan Wei, Yueting Chen, Yongyu Xu, Yang Zan, Ru Zhang, Min Wang, Qiuhong Hua, Haifeng Gu, Fajun Nan*, Xin Xie*. Small molecule compound induces chromatin de-condensation and facilitate induced pluripotent stem cell generation. Journal of Molecular Cell Biology. 2014, Accepted.
（2）Yongyu Xu, Xiaoyuan Wei, Min Wang, Ru Zhang*, Yanbin Fu, Mingzhe Xing, Qiuhong Hua, Xin Xie*. Proliferation rate of somatic cells affects reprogramming efficiency. Journal of Biological Chemistry. 2013, Apr 5;288(14):9767-78.
（3）Feifei Zhang, Wei Wei, Hui Chai, Xin Xie*. Aurintricarboxylic Acid Ameliorates Experimental Autoimmune Encephalomyelitis by Blocking Chemokine-mediated Pathogenic Cell Migration and Infiltration. Journal of Immunology. 2013 Feb 1;190(3):1017-25.
（4）Wei Wei, Changsheng Du, Jie Lv, Guixian Zhao, Zhenxin Li, Zhiying Wu, György Haskó, Xin Xie*. Blocking A2B Adenosine Receptor alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and TH-17 Differentiation. Journal of Immunology. 2013 Jan 1;190(1):138-46.
（5）Xinxiu Xu, Quan Wang, Yuan Long, Ru Zhang, Xiaoyuan Wei, Mingzhe Xing, Haifeng Gu, Xin Xie*. Stress-mediated p38 activation promotes somatic cell reprogramming. Cell Research. 2013 Jan;23(1):131-41.
（6）Jie Lv, Changsheng Du, Wei Wei, Zhiying Wu, Guixian Zhao, Zhenxin Li, Xin Xie*. The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis. Journal of Biological Chemistry. 2012 Aug 17; 287(34):28656-65.
（7）Chang-Sheng Du, Xin Xie*. G Protein-Coupled Receptors as Therapeutic Targets for Multiple Sclerosis. Cell Research. 2012 Jul; 22(7):1108-28.
（8）Ru Zhang, Guizhen Xue, Shaodeng Wang, Lihong Zhang, Changjie Shi, Xin Xie*. Novel object recognition as a facile behavior test for evaluating drug effects in AβPP/PS1 Alzheimer’s mouse model. Journal of Alzheimers Disease. 2012, 31: 801-812.
（9）Liefeng Wang, Changsheng Du, Jie Lv, Wei Wei, Ye Cui, Xin Xie*. Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis. Journal of Immunology. 2011;187(5):2336-45.
（10）Quan Wang, Xinxiu Xu, Jun Li, Jing Liu, Haifeng Gu, Ru Zhang, Jiekai Chen, Yin Kuang, Jian Fei, Cong Jiang, Ping Wang, Duanqing Pei, Sheng Ding, Xin Xie*. Lithium, an anti-Psychotic Drug, Greatly Enhances the Generation of Induced Pluripotent Stem Cells. Cell Research. 2011;21(10):1424-35.
（11）Chenlei Yin, Ru Zhang, Yongyu Xu, Qiuyan Chen, Xin Xie*. Intact Mdm2 E3 Ligase Activity Is Required for the Cytosolic Localization and Function of β-Arrestin2. Molecular Biology of the Cell. 2011 Mar 9; 22(9):1608-16.
（12）He X, Fang L, Wang J, Yi Y, Zhang S, Xie X*. Bryostatin-5 blocks stromal cell-derived factor-1 induced chemotaxis via desensitization and down-regulation of cell surface CXCR4 receptors. Cancer Research 2008 Nov 1; 68(21):8678-86.
