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张宏冰



课题组成员:硕士生5名、博士生5名、博士后1名、井艳玲主管技师、王亚南、浦洋助理研究员、张宏冰教授

负责人:张宏冰是美国宾夕法尼亚大学(University of Pennsylvania)医学院博士, 哈佛大学医学院博士后、讲师。从2006年以来,任中国医学科学院-北京协和医学院生理学博士生导师,医学分子生物学国家重点实验室成员,美国中华医学基金会(CMB) 杰出教授,国家杰出青年科学基金获得者。

目前研究方向:研究细胞信号传导的调节,探讨疾病的发生机制、早期诊断和靶向治疗,为促进基础医学到临床医学的转化、疾病的精准治疗提供依据。

课题组成员发表的代表性论文:

1.    Sun Q, Li S, Wang Y, Peng H, Zhang X, Zheng Y, Li C, Li L, Chen R, Chen X, Bai W, Jiang X, Liu L, Wei F, Wang B, Zhang Y, Li H, Ren X, Zhang H. Phosphoglyceric acid mutase-1 contributes to oncogenic mTOR-mediated tumor growth and confers non-small cell lung cancer patients with poor prognosis. Cell Death Differ. 2018 Jan 23. doi: 10.1038/s41418-017-0034-y.

2.     Xu KF, Tian X, Yang Y, Zhang H. Rapamycin for Lymphangioleiomyomatosis: Optimal time and optimal dosage. Thorax 2018;73(4):308-310.

3.     王冬梅,孟真,张宏冰。雷帕霉素靶蛋白抑制剂西罗莫司治疗晚期骨髓纤维化二例,中华医学杂志 2018;98(2):154-155。

4.     Chen R, Duan J, Li L, Ma Q, Sun Q, Ma J, Li C, Zhou X, Chen H, Jing Y, Zhao S, Wu X, Zhang H. mTOR promotes pituitary tumor development through activation of PTTG1. Oncogene 2017;36(7):979-988

5.     Xu MM, Pu Y, Han D, Shi Y, Cao X, Liang H, Chen X, Li XD, Deng L, Chen ZJ, Weichselbaum RR, Fu YX. Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling. Immunity. 2017;47(2):363-373.e5.

6.     Xu MM, Pu Y, Weichselbaum RR, Fu YX. Integrating conventional and antibody-based targeted anticancer treatment into immunotherapy. Oncogene. 2017 Feb 2;36(5):585-592.

7.     Nie M, Xu H, Chen R, Mao J, Wang X, Xiong S, Zheng J, Yu B, Cui M, Ma W, Huang Q, Zhang H, Wu X. Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations. Eur J Endocrinol. 2017:177(4):389-398.

8.     Jin F, Jiang K, Ji S, Wang L, Ni Z, Huang F, Li C, Chen R, Zhang H, Hu Z, Zha X. Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex. Hum Mol Genet. 2017;26(2):407-419

9.     Liu KM, Zhang HH, Wang YN, Wang LM, Chen HY, Long CF, Zhang LF, Zhang HB, Yan HB. Wild-type p53-induced Phosphatase 1 Deficiency Exacerbates Myocardial Infarction-induced Ischemic Injury. Chin Med J (Engl). 2017;130(11):1333-1341.

10.   Wu H, Wu Z, Li P, Cong Q, Chen R, Xu W, Biswas S, Liu H, Xia X, Li S, Hu W, Zhang Z, Habib SL, Zhang L, Zou J, Zhang H, Zhang W, Li B. Bone Size and Quality Regulation: Concerted Actions of mTOR in Mesenchymal Stromal Cells and Osteoclasts. Stem Cell Reports. 2017: 8(6):1600-1616.

11.   Pu Y, Xu M, Liang Y, Yang K, Guo Y, Yang X, Fu YX. Androgen receptor response against prostate cancer leading to early tumor relapse. Sci. Transl. Med. 2016 Apr 6;8(333):333ra47

12.   Liu Z, Mao J, Wu X, Xu H, Wang X, Huang B, Zheng J, Nie M, Zhang H. Efficacy and Outcome Predictors of Gonadotropin Treatment for Male Congenital Hypogonadotropic Hypogonadism. Medicine 2016;95(9):e2867.

13.   Chen X, Zhu Y, Wang Z, Zhu H, Pan Q, Su S, Dong Y, Li L, Zhang H, Wu L, Lou X, Liu S. mTORC1 alters the expression of glycolytic genes by regulating KPNA2 abundances. J Proteomics. 2016;136:13-24.

14.   Chen X, Wang Y, Tao J, Shi Y, Gai X, Huang F, Ma Q, Zhou Z, Chen H, Zhang H, Liu Z, Sun Q, Peng H, Chen R, Jing Y, Yang H, Mao Y, Zhang H. mTORC1 Upregulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. Gastroenterology. 2015;149(3):741–752.

15.   Hu Z, Wang Y, Huang F, Chen R, Li C, Wang F, Goto J, Kwiatkowski DJ, Wdzieczak-Bakala J, Tu P, Liu J, Zha X, Zhang H. Brain Expressed X-Linked 2 Is Pivotal for Hyperactive mTOR-mediated Tumorigenesis. J Biol Chem. 2015; 290 (42):25756-65.

16.   Chen R, Li S, Liu G, Yuan Y, Liu J, Liu T, Wu R, Sun Q, Ren X, Yi X, Zhang H. Digital karyotyping with whole genome sequencing for complex congenital disorder. J Genet Genomics. 2015; 42 (11):651-5

17.   Jin D, Tao J, Li D, Wang Y, Li L, Hu ZD, Zhou ZZ, Chang XL, Qu CF, Zhang H. Golgi protein 73 activation of MMP-13 promotes hepatocellular carcinoma cell invasion Oncotarget. 2015; 6 (32):33523-33.

18.   茅江峰,陈蓉蓉,伍学焱,刘兆祥,郑俊杰,王曦,聂敏,段婧,张宏冰。先天性低促性腺激素性性腺功能减退症男性患者的性腺轴外表现和致病基因间的关系。中华医学杂志2015; 95:3424-7.

19.   Zha X, Hu Z, Ji S, Jin F, Jiang K, Li C, Zhao P, Tu Z, Chen X, Di L, Zhou H, Zhang H. NFκB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth. Cancer Lett. 2015; 359:97-106

20.   Zhang L, Liu L, He Z, Li G, Liu J, Song Z, Jin H, Rudolph KL, Yang H, Mao Y, Zhang L, Zhang H, Xiao Z, Ju Z. Inhibition of Wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mTOR. Hepatology. 2015; 61:2030-41

21.   Mao JF, Xu HL, Duan J, Chen RR, Li L, Li B, Nie M, Min L, Zhang HB, Wu XY. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients. Asian J Androl. 2015; 17:497-502.

22.   Liu Z, Chen X, Wang Y, Peng H, Wang Y, Jing Y, Zhang H. PDK4 Protein Promotes Tumorigenesis through Activation of cAMP-response Element-binding Protein (CREB)-Ras Homolog Enriched in Brain (RHEB)-mTORC1 Signaling Cascade. J Biol Chem. 2014; 289 (43):29739-49 (Paper of the Week).

23.   Wang F, Chen X, Li C, Sun Q, Chen Y, Wang Y, Peng H, Liu Z, Chen R, Liu K, Yan H, Ye BH, Kwiatkowski DJ, Zhang H. Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex. Oncogene. 2014; 33(34):4352-8.

24.   Liu Z, Xu KF, Hu C, Chen R, Duan J, Shi Y, Wang Y, Zhang W, Moss J, Wu J, Zhang H.  Use of whole-exome sequencing for the diagnosis of atypical Birt-Hogg-Dubé syndrome.  J Genet Genomics. 2014; 41(8): 449-151

25.   Ma A, Wang L, Gao Y, Chang Z, Peng H, Zeng N, Gui YS, Tian X, Li X, Cai B, Zhang H, Xu KF. Tsc1 deficiency-mediated mTOR hyperactivation in vascular endothelial cells causes angiogenesis defects and embryonic lethality. Hum Mol Genet. 2014; 23: 693-705

26.   Chen Y, Wang F, Li C, Wang L, Zhang H, Yan H. Acquired cardiomyopathy caused by cardiac Tsc1 deficiency. J Genet Genomics. 2014; 41: 73-7 

27.   Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J, Zhang H, Wang R, Yang Z, Zhang L, Zhao Y. TSC1 controls macrophage polarization to prevent inflammatory disorder. Nature Commun. 2014; 5:4696.

28.   Wang W, Liu J, Ma A, Miao R, Jin Y, Zhang H, Xu K, Wang C, Wang J. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3. J Cell Physiol. 2014; 229: 2117-25

29.   Wang Y, Hu Z, Liu Z, Chen R, Peng H, Guo J, Chen X, Zhang H. MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1. Autophagy. 2013;9(12):2069-86.

30.   Peng H, Liu J, Sun Q, Chen R, Wang Y, Duan J, Li C, Bin Li, Jing Y, Chen X, Mao Q, Xu KF, Walker CL, Li J, Wang J, Zhang H. mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development. Oncogene. 2013; 32(39):4702-11.

31.   Li H, Wang J, Xu H, Xing R, Pan Y, Li W, Cui J, Zhang H, Lu Y. Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells. Mol Cancer. 2013; 12(1):110

32.   Dai C, Zhang B, Liu X, Ma S, Yang Y, Yao Y, Feng M, Bao X, Li G, Wang J, Guo K, Ma W, Xing B, Lian W, Xiao J, Cai F, Zhang H, Wang R. Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology. 2013; 154: 1247-1259.

33.   He J, Kang L, Wu T, Zhang J, Wang H, Gao H, Zhang Y, Huang B, Liu W, Kou Z, Zhang H, Gao S. An elaborate regulation of mTOR activity is required for somatic cell reprogramming induced by defined transcription factors. Stem Cells Dev. 2012; 21: 2630-41.

34.   Zhang Y, Du XL, Wang CJ, Lin DC, Ruan X, Feng YB, Huo YQ, Peng H, Cui JL, Zhang TT, Wang YQ, Zhang H, Zhan QM, Wang MR. Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells. Gastroenterology. 2012; 142: 521-30.

35.   Zhang L, Zhang H, Li L, Xiao Y, Rao E, Miao Z, Chen H, Sun L, Li H, Liu G, Zhao Y. TSC1/2 Signaling complex is essential for peripheral naïve CD8 T cell survival and homeostasis in mice. PLoS One. 2012; 7: e30592.

36.   Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, Chang L, Zhang Yu, Goto J, Onda H, Chen T, Wang MR, Lu Y, You H, Kwiatkowski DJ, Zhang H. Mammalian target of rapamycin upregulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011, 108: 4129-34.

37.   Ma J, Sun Q, Mi R, Zhang H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling. J Genet Genomics. 2011, 38: 533-7.

38.   Zha X, Hu Z, He S, Wang F, Shen H, Zhang H. TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade. Cancer Lett. 2011, 313: 211-7.

39.   Tian X, Shao C, Feng R, Xu K, Zhang H. Expiratory lymphatic sacs. Am J Respir Crit Care Med. 2011, 184: 1085.

40.   Wu XN, Wang XK, Wu SQ, Lu J, Zheng M, Wang YH, Zhou H, Zhang H, Han J. Phosphorylation of raptor by p38β participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation. J Biol Chem. 2011, 286:31501-11.

41.   Sun Y, Yang H, Mao Y, Xu H, Zhang J, Li G, Lu X, Sang X, Zhao H, Zhong S, Huang J, Zhang H. Increased GP73 expression in hepatocellular carcinoma tissue correlates with tumor aggression but not survival. J Gastroenterol Hepatol. 2011, 26:1207-12.

42.   Zha X, Sun Q, Zhang H. mTOR upregulation of glycolytic enzymes promotes tumor development. Cell Cycle 2011, 10: 1015-6

43.   Zheng M, Wang YH, Wu XN, Wu SQ, Lu BJ, Dong MQ, Zhang H, Sun P, Lin SC, Guan KL, Han J. Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nature Cell Biol. 2011, 13; 263-72

44.   Zha X, Wang F, Wang Y, He S, Jing Y, Wu X, Zhang H. Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis. Cancer Res. 2011, 71; 13–8.

45.   Mao Y, Yang H, Xu H, Lu X, Sang X, Du S, Zhao H, Chen W, Xu Y, Chi T, Yang Z, Cai J, Li H, Chen J, Zhong S, Mohanti SR, Lopez-Soler R, Millis JM, Huang J, Zhang H. Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma. Gut. 2010, 59:1687-93.

46.   Lai KP, Leong WF, Chau JF, Jia D, Zeng L, Liu H, He L, Hao A, Zhang H, Meek D, Velagapudi C, Habib SL, Li B. S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J. 2010, 29: 2994–3006.

47.   Ma J, Meng Y, Kwiatkowsk DJ, Chen X, Peng H, Sun Q, Zha X, Wang F, Wang Y, Jing Y, Zhang S, Chen R, Wang L, Wu E, Cai G, Malinowska-Kolodziej I, Liao Q, Liu Y, Zhao Y, Sun Q, Xu K, Dai J, Han J, Wu L, Zhao RC, Shen H, Zhang H. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010, 120: 103-14.

48.   Mi R, Ma J, Zhang D, Li L, Zhang H. Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model. J Genet Genomics. 2009, 36:355-61.

49.   Zhang J., B. Wang, Z. Xiao, Y. Zhao, B. Chen, J. Han, Y. Gao, W. Ding,Zhang H, J. Dai. Olfactory ensheathing cells promote proliferation and inhibit neuronal differentiation of neural progenitor cells through activation of Notch1. Neuroscience 2008, 153: 406-13.

50.   Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL, Griffin JD, Kwiatkowski DJ. PDGF receptors are critical for PI3K/AKT activation and negatively regulated by mTOR. J Clin Invest. 2007, 117: 730-8.

51.   Lee L, Sudentas P, Donohue B, Asrican K, Worku A, Walker V, Sun Y, Schmidt K, Albert MS, El-Hashemite N, Lader AS, Onda H, Zhang H, Kwiatkowski DJ, Dabora SL. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005, 42: 213-27.

52.   Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, Lewin-Kowalik J, Kotulska K, Kwiatkowski DJ. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropath Exp Neur. 2004, 63:1236-42.

53.   El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJ. Perturbed IFNg-Jak-stat signaling in tuberouse sclerosis mouse models: synergistic effects of rapamycin-IFNg treatment. Cancer Res. 2004, 64: 3436-43.

54.   Finlay GA, York B, Karas RH, Fanburg BL, Zhang H, Kwiatkowski DJ, Noonan DJ. Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2. J Biol Chem 2004, 279: 23114-22

55.   Zhang H, Cicchetti G, Onda H, Koon HB, Asrikan K, Bajraszewski N, Vazquez P. Carpenter C, Kwiatkowski DJ. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signalling through downregulation of PDGFR. J Clin Invest. 2003, 112: 1223-33.

56.   El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ. Loss of tuberous sclerosis complex genes induces vascular endothelial growth factor production through mTOR pathway. Cancer Res. 2003, 63: 5173-7.

57.   El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet. 2003, 361: 1348-9.

58.   Onda H, Crino P, Zhang H, Murphey R, Rastelli L, Rothberg BG, Kwiatkowski DJ. Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci. 2002, 21: 561-74.

59.   Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Onda H. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in TSC1 null cells. Hum Mol Genet. 2002, 11: 525-34.

60.   Houvras Y, Benezra M, Zhang H, Manfredi JJ, Weber BL., Licht JD. BRCA1 physically and functionally interacts with the ATF1 transcription factor. J Biol Chem. 2000, 275: 36230-7.

61.   Sun J, Paddock C, Shubert J, Zhang H, Amin K, Newman PJ, Albelda SM. Contributions of the extracellular and cytoplasmic domains of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) in regulating cell-cell localization. J Cell Sci. 2000, 113:1459-69.

62.   Liu L, Scolnick DM, Trievel RC, Zhang HB, Marmorstein R, Halazonetis TD, Berger SL. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol. 1999, 19:1202-9.

63.   Zhang HB, Tombline G, Weber BL. BRCA1, BRCA2, and DNA Damage Response: Collision or Collusion? Cell. 1998, 92, 433-6.

64.   Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber BL, El-Deiry WS. BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene. 1998, 16: 1713-21.

65.   Somasundaram K, Zhang HB (equal contribution as the first author), Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature. 1997, 389: 187-90.

66.   Thakur S, Zhang HB, Peng Y, Le H, Carroll B, Ward T, Yao J, Farid LM, Couch F, Wilson RB, Weber BL. Localization of BRCA1 and a splice variant identifies the nuclear localization signal. Mol Cell Bio. 1997, 17: 444-52.

67.   Elshami AA, Saavedra A, Zhang H, Kucharczuk JC, Spray DC, Fishman GI, Amin KM, Kaiser LR, Albelda SM. Gap-junctions play a role in the bystander effect of the herpes-simplex virus thymidine kinase ganciclovir system in-vitro. Gene Therapy.1996, 85-92.

68.   Elshami AA, Kucharczuk JC, Zhang HB, Smythe WR, Hwang HC, Litzky LA, Kaiser LR, Albelda SM. Treatment of pleural mesothelioma in an immunocompetent rat model utilizing adenoviral transfer of the herpes-simplex virus thymidine kinase gene. Human Gene Therapy. 1996, 141-8.

69.   Kucharczuk JC, Elshami AA, Zhang HB, Smythe WR, Hwang HC, Tomlinson JS, Amin KM, Litzky LA, Albelda SM, Kaiser LR. Pleural based mesothelioma in immune competent rats--a model to study adenoviral gene-transfer. Ann Thoracic Surg. 1995, 60: 593-8.

70.   Muschel RJ, Zhang HB, McKenna WG. Differential effect of ionizing radiation on the expression of cyclin A and cyclin B in HeLa cells. Cancer Res. 1993, 53:1128-35.

71.   Muschel RJ, Zhang HB, Iliakis G, McKenna WG. Effects of ionizing radiation on cyclin expression in HeLa cells. Radiation Res. 1992, 132:153-7.

72.   Muschel RJ, Zhang HB, Iliakis G, McKenna WG. Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation. Cancer Res. 1991, 51:5113-7.