刘江怀实验室

研究方向：

       主要来源于造血干细胞的免疫系统是维持机体健康的重要组成部分。相反，它的紊乱也是许多疾病过程的致病因素。我们实验室致力于进一步挖掘免疫系统特殊的调控机制、尝试人工改造免疫系统的新方法，期望可以对免疫相关疾病的治疗产生积极影响。实验室目前的工作主要可以分成两块:

1. 针对免疫细胞的代谢学研究。机体在应激的状态下，会发生能量代谢的重排，旨在支持机体应对环境改变。作为机体应激的重要组成部分，免疫系统的功能必然与能量代谢有密切的联系。我们在这个逐渐兴起的领域开展了系列研究。我们的阶段性成果首次揭示了在抗病毒先天免疫激活条件下，巨噬细胞特异性的糖代谢重编程及其重要性（Jiang H et al., J Immunol 2016）。该研究带动了目前实验室中正在进行的一系列相关研究：如免疫代谢与自身免疫性疾病，以及与宏观代谢综合症（如II型糖尿病）的关联。
2. 新一代顺式调控元件靶向技术在免疫学研究及细胞治疗中的应用。人类基因组中蕴藏着远远大于基因数目的顺式调控序列。这些序列在很大程度上决定各个基因在生理及病理条件下的表达，是基因之外控制生命活动的关键因素。最近，我们实验室与黄行许教授课题组合作，基于改造后的基因编辑平台（dCas9/sgRNA），率先在人源细胞中建立了高效、非突变型的顺式调控元件靶向技术（Du Y et al., Cell Res 2015）。我们正在进一步扩展顺式元件靶向技术在免疫系统中的应用。此外，我们在尝试利用类似的技术平台搭建人工转录调控回路，重新‘编排’细胞的免疫响应，为研发更加‘智能化’的细胞治疗提供基础。

1.     Jiang H, Shi H, Sun M, Wang Y, Meng Q, Guo P, Cao Y, Chen J, Gao X, Li E* and Liu J*. PFKFB3-driven macrophage glycolytic metabolism is a crucial component of innate antiviral defense. J Immunol 2016, 197(7), 2080-90.

2.     Dong Z, Huang M, Liu Z, Xie P, Dong Y, Wu X, Qu Z, Shen B, Huang X, Zhang T, Li J, Liu J, Yanase T, Zhou C, Xu Y. Focused screening of mitochondrial metabolism reveals a crucial role for a tumor suppressor Hbp1 in ovarian reserve. Cell Death Differ 2016, In press, doi: 10.1038/cdd.2016.47.

3.     Zhang Y, Wang Y, Zhang C, Wang J, Pan D, Liu J* and Feng F*. Targeted Gene Delivery to Macrophages by Biodegradable Star-Shaped Polymers. ACS Appl Mater Inter 2016, 8(6):3719-24.

4.     Du Y, Meng Q, Zhang J, Sun M, Shen B, Jiang H, Kang Y, Gao J, Huang X* and Liu J*. Functional annotation of cis-regulatory elements in human cells by dCas9/sgRNA. Cell Res 2015, 25(7):877-80. †Equal contribution.

5.     Tong, Y., Li, F., Lu, Y., Cao, Y., Gao, J.* and Liu, J.*, Rapamycin-sensitive mTORC1 signaling is involved in physiological primordial follicle activation in mouse ovary. Mol. Reprod. Dev. 2013, 80: 1018–1034.

6.     HuangFu, W. C., Qian, J., Liu, C., Liu, J., Lokshin, A. E., Baker, D. P., Rui, H., and Fuchs, S. Y. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 2012, 31(2):161-72.

7.     Jiang, H., Lu, Y., Yuan, L., and Liu, J.* Regulation of Interleukin-10 Receptor Ubiquitination and Stability by Beta-TrCP-Containing Ubiquitin E3 Ligase. PLoS ONE 2011, 6: e27464.

8.     Qian, J., Zheng, H., HuangFu, W.-C., Liu, J., Carbone, C. J., Leu, N. A., Baker, D. P., and Fuchs, S. Y. Pathogen Recognition Receptor Signaling Accelerates Phosphorylation-Dependent Degradation of IFNAR1. PLoS Pathog 2011, 7: e1002065.

9.     Bhattacharya S, Huangfu WC, Liu J, Veeranki S, Baker DP, Koumenis C, Diehl JA, Fuchs SY. Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of Type I interferon receptor. J Biol Chem 2010; 285(4): 2318-25.

10.   Liu J, Carvalho LP, Bhattacharya S, Carbone CJ, Kumar KG, Leu NA, Yau PM, Donald RG, Weiss MJ, Baker DP, McLaughlin KJ, Scott P, Fuchs SY. Mammalian Casein Kinase 1a and Its Leishmanial Ortholog Regulate Stability of IFNAR1 and Type I Interferon Signaling. Mol Cell Biol 2009; 29:6401-12.

11.   Liu J, HuangFu WC, Kumar KG, Qian J, Casey JP, Hamanaka RB, Grigoriadou C, Aldabe R, Diehl JA, Fuchs SY (2009). Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe; 5:72-83.

12.   Liu J, Plotnikov A, Banerjee A, Suresh Kumar KG, Ragimbeau J, Marijanovic Z, Baker DP, Pellegrini S, Fuchs SY (2008). Ligand-independent pathway that controls stability of interferon alpha receptor. Biochem Biophys Res Commun; 367:388-93.

13.   HuangFu WC*, Liu J*, Harty RN, Fuchs SY (2008). Cigarette smoking products suppress anti-viral effects of Type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS Lett; 582:3206-10. *These authors contributed equally to this work.

14.   Liu J, Suresh Kumar KG, Yu D, Molton SA, McMahon M, Herlyn M, Thomas-Tikhonenko A, Fuchs SY (2007). Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. Oncogene; 26:1954-8.

15.   Kumar KG, Liu J, Li Y, Yu D, Thomas-Tikhonenko A, Herlyn M, Fuchs SY (2007). Raf inhibitor stabilizes receptor for the type I interferon but inhibits its anti-proliferative effects in human malignant melanoma cells. Cancer Biol Ther; 6:1437-41.

16.   Kumar KG, Barriere H, Carbone CJ, Liu J, Swaminathan G, Xu P, Li Y, Baker DP, Peng J, Lukacs GL, Fuchs SY (2007). Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis. J Cell Biol; 179:935-50.

17.   Noubissi FK, Elcheva I, Bhatia N, Shakoori A, Ougolkov A, Liu J, Minamoto T, Ross J, Fuchs SY, Spiegelman VS (2006). CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling. Nature; 441:898-901.

18.   Liu J, Fuchs SY (2006). Cross-talk between APC/C and CBP/p300. Cancer Biol Ther; 5:760-2.

19.   Liu J, Rich CB, Buczek-Thomas JA, Nugent MA, Panchenko MP, Foster JA. Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts (2003). Am J Physiol Lung Cell Mol Physiol; 285:L1106-15.