科学研究
血液干细胞代谢调控和免疫靶向组
  作者:  2020-12-15


研究组长简介

           

郑俊克

血液干细胞代谢调控和免疫靶向组

电话:021-63846590-776915

邮箱:zhengjunke@shsmu.edu.cn

 




郑俊克,上海交通大学医学院,研究员,国家杰青项目入选者。2007年毕业于上海交通大学医学院;2007-2012年在美国西南医学中心从事博士后工作;20126月起受聘于上海交通大学医学院细胞分化和凋亡教育部重点实验室。主要从事造血干细胞干性维持的机制及其恶性转化为白血病干细胞的规律研究。近年来,围绕血液干细胞代谢和微环境成分-免疫抑制性受体介导的信号通路在干性维持和免疫靶向中的作用和机制方面,取得系列重要发现,并以通讯/共同通讯作者在NatureCell Metabolism(封面文章)、JCIBloodLeukemiaEMBO J等著名杂志上发表论文13余篇,目前累计发表论文50篇,他引1300余次。所获资助项目还包括基金委重点项目、优青、面上项目、上海市优秀青年学术带头人、上海市东方学者、曙光计划以及浦江人才计划等。担任中国生理学会血液专业委员会委员、中国病理生理学会青年工作委员会秘书长、中国细胞生物学学会细胞代谢分会委员等学术职务。获上海市第十五届银蛇奖、上海市五四青年奖章和吴孟超医学青年基金奖等。

 

研究方向与进展

郑俊克课题组近几年的研究揭示了骨髓微环境中造血干细胞代谢学特性及其与干性维持间的重要关系,特别是造血干细胞独特的糖/氨基酸等代谢方式及其调控网络;同时阐明了微环境重要成分Angptls/APOE及其免疫抑制性受体LILRBs/JAM3等在体内外维持造血干细胞干性的分子机制,以及在疾病状态下白血病干细胞干性维持中的调控规律和潜在免疫治疗新靶点等。这些研究为发展造血干细胞体外扩增新技术及其临床应用,寻找靶向白血病干细胞的特异免疫治疗靶点以更有效地治疗白血病,提供了有力的条件。

目前本团队以造血干细胞/白血病干细胞代谢平台为支持,结合动物模型、代谢组学、代谢感受器、骨髓微环境成像和免疫治疗(抗体和CAR-T)等相关前沿技术,聚焦于三个主要研究方向:1)造血干细胞和白血病干细胞糖、氨基酸等内在代谢调控规律;2)骨髓微环境组分调控造血干细胞稳态和恶变规律;3)白血病免疫治疗机制探讨和策略开发。

 

科研项目

  1. 国家基金委,重点项目,生理和应激条件下造血干细胞糖代谢异质性特征和分子基础(32030030),2021.01-2025.12295万,在研,主持

  2. 国家基金委,杰出青年科学基金(81825001),2019.1-2023.12350万,在研,主持

  3. 上海市科委,骨髓代谢性酸环境调控白血病干细胞干性维持机制,上海市优秀青年学术带头人(19XD1422100),2019.05-2022.04, 40万,在研,主持

  4. 科技部干细胞及转化研究重点专项,异染色质与端粒调控干细胞多能性的机制(2018YFA0107000),2018.1-2022.12176万,在研,骨干

  5. 科技部发育和代谢重点专项,跨器官通讯调控应激状态下骨髓HSC活化和迁徙的作用和机理(2019YFA0801800),2019.12-2024.12456万,在研,子课题负责人

  6. 国家基金委,创新研究群体项目(81721004),2018.1-2023.12100万,在研,骨干

  7. 国家自然科学基金面上项目,骨髓微环境中血管生成素样蛋白2对造血干细胞干性维持的作用和意义(81570093),2016.01-2019.1260万,结题,主持

  8. 国家自然科学基金优秀青年科学基金,造血干细胞和白血病干细胞生物学(81422001),2015.01-2017.12100万,结题,主持

  9. 科技部重大科学研究计划,诱导性前脑神经祖细胞体内微环境的组分解析、条件优化和功能模拟(2014CB965000),2014.01-2018.0865万,结题,骨干,参与

  10. 国家自然科学基金面上项目,B7-H1等表面免疫分子在白血病干细胞多能性维持中的作用和机制(81370654),2014.01-2017.1270万,结题,主持

  11. 上海市教委曙光计划,NADH调控在急性髓系白血病干细胞多能性维持中的作用(13G20),2014.09-2016.0915万,结题,主持

  12. 中组部青年千人计划,2013,生物学,200万,结题,主持

  13. 上海市教委东方学者岗位计划,2013,生物学,100万,结题,主持

  14. 上海市科委浦江人才计划(13PJ1405600),急性粒细胞性白血病干细胞的代谢调控,2013.09-2015.0820万,结题,主持

     

代表性论文、专著与专利

  1. H Dan#, Sun G#, Hao X#, He X# , Zheng Z, Chen C, Yu Z, Xie L, Ma S, Liu L, Zhou B O, Chen H*, Zheng J*, Cheng T*. ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression. J Clin Invest ,2020, in press (*,co-corresponding author)

  2. Gu H#, Chen C#, Hao X#, Su N#, Huang D, Zou Y, Lin S, Chen X, Zheng D, Liu L, Yu Z, Xie L, Zhang Y, He X, Lai Xi, Zhang X, Chen GQ, Zhao Y, Yang Y, Loscalzo J, Zheng J, MDH1-mediated malate-aspartate NADH shuttle maintains the activities of fetal liver hematopoietic stem cells, Blood, 136(5):553-571,2020

  3. Hao X, Gu H, Chen C, Huang D, Zhao Y, Xie L, ZouY,  Shu H, Zhang Y, He X, Lai X, Zhang X, Zhou B, Zhang CC, Chen GQ, Yu Z, Yang Y, Zheng J. Metabolic imaging reveals a unique preference of symmetric cell division and homing of leukemia-initiating cells in an endosteal niche. Cell Metab., 29(4):950-965, 2019 (封面文章)

  4. Huang D, Chen C, Hao X, Gu H, Xie L, Yu Z, Zheng J. Metabolic Regulations in Hematopoietic Stem Cells. Adv Exp Med Biol.,1143:59-74, 2019

  5. Zhang LS, Kang X, Lu J, Zhang Y, Wu X, Wu G, Zheng J, Tuladhar R, Shi H, Wang Q, Morlock L, Yao H, Huang LJ, Maire P, Kim J, Williams N, Xu J, Chen C, Zhang CC, Lum L. Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. EBioMedicine. 39:145-158, 2019

  6. Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, He L, Chen Y, Chen H, Luo W, Lu Z, Xie J, Churchill H, Xu Y, Zhou Z, Wu G, Yu C, John S, Hirayasu K, Nguyen N, Liu X, Huang F, LLi L, HDeng H, Tang H, Sadek A, Zhang L, Huang T, Zou Y, Chen B, Zhu H, Arase H, Xia N, Jiang Y, Collins R, You M, Homsi J, Unni N, Lewis C, Chen GQ, YX, X. Liao X, An Z, Zheng J, Zhang N, and Zhang CC. LILRB4 signaling in leukemia cells mediates T cell suppression and tumor infiltration. Nature, 562(7728):605-609, 2018 (*,co-corresponding author)

  7. Peng Y, Yu H, Hao X, Dong W, Yin X, Lin M, Zheng J*, Zhou B*. Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty. EMBO J., e98984, 2018(*,co-corresponding author)

  8. Liu X, Zhang F, Zhang Y, Li X, Chen C, Zhou M, Yu Z, Zhao Y, Hao X, Tang B, Zhu L, Liu G, Xie L, Gu H, Shao H, Xia F, Yin C, Tao M, Xie J, Zhang CC, Yang Y, Sun H, Chen GQ, Zheng J. PPM1K regulates hematopoiesis and leukemogenesis through CDC20-mediated ubiquitination of MEIS1 and p21. Cell Rep, 23(5):1461-1475, 2018

  9. Zhang Y, Xia F, Liu X, Yu Z, Xie L, Liu L, Chen C, Jiang H, Hao X, He X, Zhang F, Gu H, Zhu J, Bai H, Zhang CC, Chen GQ, Zheng J. JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling. J Clin Invest., 128(5):1737-1751, 2018

  10. Xia F, Zhang Y, Xie L, Jiang H, Zeng H, Chen C, Liu L, He X, Hao X, Fang X, Liu X, Zhang F, Gu H, Wan J, Chen Y, Zhang CC, Chen GQ, Lu Y, Yu Z, Zheng J. B7-H4 enhances the differentiation of murine leukemia-initiating cells via the PTEN/AKT/RCOR2/RUNX1 pathways. Leukemia, 31:2260–2264, 2017

  11. Zhang F, Liu X, Chen C, Zhu J, Yu Z, Xie J, Xie L, Bai H, Zhang Ya, Fang X, Gu H, Wang C, Weng W, Zhang CC, Chen GQ, Liang A, Zheng J. CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1 signaling. Haematologica, 102(4):707-718, 2017

  12. Dai J, Lu Y, Wang C, Chen X, Fan X, Gu H, Wu X, Wang K, Gartner TK, Zheng J, Chen G, Wang X, Liu J. Vps33b regulates Vwf-positive vesicular trafficking in megakaryocytes. J Pathol. J Pathol., 240(1):108-19, 2016

  13. Fang X, Chen C, Xia F, Yu Z, Zhang Y, Zhang F, Gu H, Wan J, Zhang X, Weng W, Zhang CC, Chen G, Liang A, Xie L, Zheng J. CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling. J Hemato & Oncol., 9:124, 2016

  14. Gu H, Chen C, Hao X, Wang C, Zhang X, Li Z, Shao H, Zeng H, Yu Z, Xie L, Xia F, Zhang F, Liu X, Zhang Y, Jiang H, Zhu J, Wan J, Wang C, Weng W, Xie J, Tao M, Zhang CC, Liu J, Chen GQ, Zheng J. Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. J Clin Invest., 126(12): 4537-4553, 2016

  15. Xia F, Wang N, Han B, Li Q, Chen Y, Zhu C, Chen Y, Pu X, Cang Z, Zhu C, Lu M, Meng Y, Guo H, Chen C, Lin D, Zheng J, Kuang L, Tuc W, Li B, Hu L, Shen Z, Lu Y. Hypothalamic-Pituitary-Gonadal Axis in Aging Men and Women: Increasing Total Testosterone in Aging Men. Neuroendocrinology, 104(3):291-301, 2017

  16. Zhang F, Zheng J*, Kang X, Deng M, Lu Z, Kim J, Zhang CC. Inhibitory leukocyte immunoglobulin-like receptors in cancer development. Sci China Life Sci, 58(12): 1216-1225, 2015 (*,co-corresponding author)

  17. Kocabas F, Xie L, Xie J, Yu Z, DeBerardinis R J, Kimura W, Thet S, Elshamy A F, Muralidhar S, Liu X, Chen C, Sadek H A , Zhang CC and Zheng J. Hypoxic Metabolism in Human Hematopoietic Stem Cells. Cell Biosci, 5:39, 2015

  18. Shen J, Zheng J, Saxena R, Zhang CC, Tang L. Novel source of human hematopoietic stem cells from peritoneal dialysis effluents. Stem Cell Res, 15(2): 299-304, 2015

  19. Fan X, Shi P, Dai J, Lu Y, Chen X, Liu X, Zhang K, Wu X, Sun Y, Wang K, Zhu L, Zhang CC, Zhang J, Chen GQ, Zheng J*, Liu J. Paired immunoglobin-like receptor B regulates platelet activation. Blood, 124(15):2421-2430 , 2014 (*,co-corresponding author)

  20. Deng M, Lu Z, Zheng J*, Wan X, Chen X, Hirayasu K, Sun H, Lam Y, Chen L, Wang Q, Song C, Huang N, Gao GF, Jiang Y, Arase H, Zhang CC. A motif in LILRB2 critical for Angptl2 binding and activation. Blood, 124(6):924-35, 2014 (*,co-corresponding author)

  21. Zheng J, Lu Z, Kocabas F, Böttcher RT, Costell M, Kang X, Liu X, Deberardinis RJ, Wang Q, Chen G, Sadek H, Zhang CC. Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow. Blood, 13;123(7):992-1001,2014

  22. Wang Q, Zhou Z, Zheng Y, Zheng J, Zhang CC. Relationship Between the Structural Specialties and Morphologies Based on a Group of Luminescent Imidazole Derivatives with Sensing Properties. Sci Adv Mater, 6(6): 1133-1139, 2014

  23. Chen X, Zheng J, Zou Y, Song C, Hu X, Zhang CC. IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells. J Hematol Oncol., 8;6(1):72, 2013

  24. Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Kang X, Silvany R, Wan X, Ye J, Cantó AP, Chen SH, Wang HY, Ward ES, Zhang CC. Immune inhibitory receptors bind to angiopoietin-like proteins and support the stemness of hematopoietic and leukemia stem cells. Nature, 485(7400):656-660, 2012

  25. Kocabas F#, Zheng J#, Thet S, Copeland NG, Jenkins NA, DeBerardinis RJ, Zhang C, Sadek HA. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood, 13(25):4963-4972, 2012 (#, co-first author)

  26. Zheng J, Umikawa M, Zhang S, Huynh H, Silvany R, Chen BP, Chen L, Zhang CC. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell, 9(2):119-130, 2011

  27. Zheng J, Huynh H, Umikawa M, Silvany R, Zhang CC. Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood, 117(2):470-479, 2011

  28. Zheng J, Song C, Zhang CC. A new chapter: hematopoietic stem cells are direct players in immunity. Cell Biosci., 1: 33, 2011

  29. Zhang S, Yajima H, Huynh H, Zheng J, Callen E, Chen HT, Wong N, Bunting S, Lin YF, Li M, Lee KJ, Story M, Gapud E, Sleckman BP, Nussenzweig A, Zhang CC, Chen DJ, Chen BP. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J.Cell.Biol., 193(3):295–305, 2011

  30. Huynh H#, Zheng J#, Umikawa M, Silvany R, Xie XJ, Wu CJ, Holzenberger M, Wang Q, Zhang CC. Components of the hematopoietic compartment in tumor stroma and tumor-bearing mice. PLoS ONE, 6(3): e18054, 2011 (#, co-first author)

  31. Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, Holzenberger M, Zhang W, Zhang CC. IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood, 118(12):3236-3243, 2011

  32. Simsek T#, Kocabas F#, Zheng J#, Deberardinis RJ, Mahmoud AI, Olson EN, Schneider JW, Zhang CC, Sadek HA. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell, 7(3):380-390, 2010 (#, co-first author)

  33. Lou Z, Zhang CC, Tirado CA, Slone T, Zheng J, Zaremba CM, Oliver D, Chen W. Infantile mixed phenotype acute leukemia (bilineal and biphenotypic) with t(10;11)(p12;q23);MLL-MLLT10. Leuk Res., 34(8): 1107-1109, 2010

  34. Huynh H, Iizuka S, Kaba M, Kirak O, Zheng J, Lodish HF, Zhang CC. Insulin-like growth factor-binding protein 2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells, 26(6): 1628-1635, 2008

  35. Zheng J, Xia X, Ding H, Yan A, Hu S, Gong X, Zong S, Zhang Y, Sheng HZ. Erasure of the paternal transcription program during spermiogenesis: the first step in the reprogramming of sperm chromatin for zygotic development. Dev Dyn., 237(5): 1463-1476, 2008

  36. Yang Y#, Zheng J#, Zhou X, Yang Z, Tan Y, Liu A, Gao X, Chang Z, Sheng HZ. Potential treatment of liver related disorders with in vitro expanded human liver precursors. Differentiation, 75(10): 928-938, 2007 (#, co-first author)

  37. Sun F, Fang H, Li R, Gao T, Zheng J, Chen X, Ying W, Sheng HZ. Nuclear reprogramming: the zygotic transcription program is established through an "erase-and-rebuild" strategy. Cell Res., 17(2): 117-134, 2007

  38. Gao T#, Zheng J#, Xing F#, Fang H, Sun F, Yan A, Gong X, Ding H, Tang F, Sheng HZ. Nuclear reprogramming: the strategy used in normal development is also used in somatic cell nuclear transfer and parthenogenesis. Cell Res., 17(2): 135-150, 2007(#, co-first author)

  39. Chen B#, Shi J#, Zheng J#, Chen Y, Wang K, Yang Q, Chen X, Yang Z, Zhou X, Zhu Y, Chu J, Liu A, Sheng HZ. Differentiation of liver cells from human primordial germ cell-derived progenitors. Differentiation, 75(5): 350-359, 2007 (#, co-first author)

出版著作

  1. Huynh      H, Kaba M, Rudra S, Zheng J, Wu      CJ, Lodish HF, Zhang CC. IGFBP2 Supports ex vivo Expansion of      Hematopoietic Stem Cells, Book Title: IGFs: Local Repair and Survival      Factors Throughout Life Span. Springer-Verlag      Berlin Heidelberg, 2010

  2. Kocabas      F, Zheng J, Zhang CC and Sadek      HA. Metabolic Characterization of Hematopoietic Stem Cells. Hematopoietic Stem Cell Protocols.      Springer. 2014

  3. Huang      D, Chen C, Zheng J. Leukemia Stem Cells in Hematologic      Malignancies: metabolic regulations in hematopoietic stem cells, Springer,      2019, ISBN 978-1-4939-1132-5.

  4. Zhang Y, Zheng J. Regulation      of Cancer Immune Checkpoints: Functions      of Immune Checkpoint, Springer, 2020, ISBN 978-981-15-3265-8.

专利:

  1. Chen SH, Zhang CC, Zheng J, Masato U, Kang X. 2012. Compositions and methods for modulating pro-inflammatory immune response. U.S. patent application 61/653,337

  2. Zhang CC, Liu Y, Zheng J, Deng M, Chen C, Liu W. 2014. Novel compound supports hematopoietic stem cells and red blood cells. U.S. patent application 62/003,969

  3. Zhang CC, Liu Y, Zheng J, Deng M, Chen C, Liu W. 2015. Novel compound supports hematopoietic stem cells and red blood cells. Canada, patent application 2,950,269

  4. Zhang CC, Liu Y, Zheng J, Deng M, Chen C, Liu W. 2014. Novel compound supports hematopoietic stem cells and red blood cells.15798855.1-1453 PCT/US201503352

  5. Bernstein ID, Zhang CC, Zheng J, Deng M, Lu Z. 2014. LILRB2 and Notch-mediated expansion of hematopoietic precursor cells. U.S. patent application 62/005,746

  6. Zhang CC, Deng M, An Z, Xiong W, Zhang N, Zheng J, Anti-LILRB antibodies and their use in detecting and treating cancer. 2015 U.S. patent application 62/129,572

 

团队介绍

目前团队包括副研、助研、技术员、博士后、博士和硕士研究生等共有15人,课题组积极营造团结互助、锐意进取、努力攻艰的实验室氛围,培养了多名优秀青年科研人才,大大提升了团队科研水平。副研究员入选基础医学院优秀青年教师计划,也获得国家自然科学基金面上项目和上海市科委自然科学基金面上项目资助;助理研究员获得国家自然科学基金青年项目和上海市科委自然科学基金面上项目资助;所指导的4名博士后中(3名已出站),1名获得国家自然科学基金青年项目,1名获国家博士后创新人才计划资助,1名获中国博士后科学基金面上项目(一等)资助;课题组精心为所有的指导研究生制定个性化培养计划,培养出了多名优秀学生。课题组已培养毕业硕士生1名和博士生9名(其中3名和4名分别在美国和中国从事博士后工作,2名博士后获国家自然科学基金青年项目,1名博士获国家自然科学基金面上项目并晋升为副研究员);3名学生获得国家奖学金,1名获上海市优秀毕业生,1名获中国科学院大学优秀毕业生和院长优秀奖,2名获上海交通大学优秀博士论文;目前,指导在读博士生6名及硕士生1名;指导的学生多次在国内外学术会议口头报告或墙报评比中获奖。