Lu, Kun Ping - Harvard Medical School - Department of Medicine

个人简介

Education M.D. Fujian Medical College (China), 1979-1984 M.Sc. (Pharmacology) Suzhou Medical College, 1984-1987 Ph.D. Candidate (Cell Biology) Baylor College of Medicine, 1989-1991 Ph.D. (Cell Biology) Duke University, 1991-1992 Academic Appointments Assistant Professor of Medicine, Harvard Medical School, 1996-2001 Associate Physician, Beth Israel Deaconess Medical Center, 1996-present Associate Professor of Medicine, Harvard Medical School, 2001-2008 Professor of Medicine, Harvard Medical School, 2008-present Chief of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, 2015-Present Director of Translational Therapeutics, Cancer Research Institute, ,Beth Israel Deaconess Medical Center, 2015-Present Awards and Honors National Institutes of Health Fellow, 1993-1994 Leukemia Society of America Fellow, 1995-1996 Leukemia and Lymphoma Society of America Scholar, 1998-2003 Pew Scholar in Biomedical Sciences, 1999-2003 Elected Member of American Society for Clinical Investigation, 2007-present Honorary Master’s Degree, Harvard Medical School, Harvard University, 2008 Elected AAAS Fellow, American Association for the Advancement of Science, 2012-present Elected Member of Association of American Physicians, 2013-present

研究领域

My laboratory has pioneered in elucidating the role of protein conformational regulation after proline-directed phosphorylation in cell signaling in health and disease, and also identified promising novel targeted therapies for treating cancer, autoimmune disorders, traumatic brain injury and Alzheimer’s disease. Protein phosphorylation regulates diverse cellular processes in health and disease. Our lab has discovered a unique enzyme called Pin1 that introduces a pivotal new twist in phosphorylation signaling by converting phosphorylated proteins between two functionally distinct conformations, cis and trans. Deregulation of this novel signaling mechanism leads to accumulation of proteins in the pathogenic conformations, thereby having profound impact on the development of many diseases, especially those related to aging or stress such as Alzheimer’s disease, traumatic brain injury, cancer and autoimmune disorders. More significantly, our lab has recently developed innovative antibody technology that can specifically detect and eliminate these pathogenic conformations, such as cis tau protein for early diagnosis and treatment of brain injury and Alzheimer’s disease. By developing high-throughput drug screens, we have also identified Pin1 small molecular inhibitors that potently block multiple disease-driving pathways in cancer, asthma and lupus. These discoveries have suggested a promising new paradigm for the development of diagnostics and therapeutics that specifically target the pathogenic protein conformations in a wide range of diseases. The current projects focus on translating our new discoveries into clinical products for improving human health, notably Pin1 inhibitors to stop multiple cancer-driving pathways and conformation-specific antibody for early diagnosis and treatment of Alzheimer’s disease and traumatic brain injury.

近期论文

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Wei, S, Yoshida, N., Finn, G., Kozono, S., Nechama, M., Kyttaris, V. C., Zhou, X. Z., Tsokos, G. C. and Lu, K. P.. Pin1-targeted therapy for systemic lupus erythematosus. Arthritis Rheumatol. 2016 May [Epub ahead of print] Zhou, X. Z. and Lu, K. P.. The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target. Nat Rev Cancer. 2016 Jul 16: 463-78. Lu, K. P., Kondo, A., Albayram, O., Liu, H., and Zhou, X. Z.. Therapeutic potential of antibody against early driver of neurodegeneration cis P-tau in early treatment and prevention of Alzheimer’s disease and brain injury. JAMA Neurology. 2016 (in press). Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, Yao Y, Lin YM, Driver JA, Sun Y, Wei S, Luo ML, Albayram O, Huang P, Rotenberg A, Ryo A, Goldstein LE, Pascual-Leone A, McKee AC, Meehan W, Zhou XZ, Lu KP. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015 Jul 523(7561):431-6. Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, Luo M, You MH, Yao Y, Kondo A, Hu H, Bozkurt G, Moerke NJ, Cao S, Reschke M, Chen CH, Rego EM, Lo-Coco F, Cantley LC, Lee TH, Wu H, Zhang Y, Pandolfi PP, Zhou XZ, Lu KP. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nature Medicine. 2015 May 21(5):457-66. Marsolier J., Perichon M., DeBarry J. D., Villoutreix B. O., Chluba J., Lopez T., Garrido C., Zhou X. Z., Lu K. P., Fritsch L., Ait-Si-Ali S., Mhadhbi M., Medjkane S., Weitzman J. B.. Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation. Nature. 2015 Apr 520: 378-382. Balastik, M., Zhou, X. Z., Alberich-Jorda, M., Weissova, R., Žiak, J., Pazyra-Murphy, M. F., Cosker, Olga Machonova, K. E., Kozmikova, I., Chen, C. H., Pastorino, L., Asara, J. M., Cole, A., Sutherland, C., Sega, R. A., and Lu, K. P.. Prolyl isomerase Pin1 regulates axon guidance by stabilizing CRMP2A selectively in distal axons. Cell Rep. 2015 Oct 13: 812-828. Hilton, B. A., Li, Z., Musich, P. R., Wang, H., Cartwright, B. M., Serrano, M., Zhou, X. Z., Lu, K. P., and Zou, Y.. ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1. Mol Cell. 2015 Oct 60: 35-46. Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. Cell Reports. 2015 Apr 11(1):111-24. Driver JA, Zhou XZ, Lu KP. Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochim Biophys Acta. 2015 Oct [Epub ahead of print] Chen CH, Li W, Sultana R, You MH, Kondo A, Shahpasand K, Kim BM, Luo ML, Nechama M, Lin YM, Yao Y, Lee TH, Zhou XZ, Swomley AM, Allan Butterfield D, Zhang Y, Lu KP. Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis. 2015 Apr 76C:13-23. Luo ML, Gong C, Chen CH, Lee DY, Hu H, Huang P, Yao Y, Guo W, Reinhardt F, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res. 2014 Jul 1;74(13):3603-16. Jalouli M, D?ry MA, Lafleur VN, Lamalice L, Zhou XZ, Lu KP, Richard DE. The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity. Cell Signal. 2014 Aug;26(8):1649-56. Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014 Apr 24;508(7497):541-5. Driver JA, Zhou XZ, Lu KP. Regulation of protein conformation by Pin1 offers novel disease mechanisms and therapeutic approaches in Alzheimer's disease. Discov Med. 2014 Feb;17(92):93-9. Toko H, Konstandin MH, Doroudgar S, Ormachea L, Joyo E, Joyo AY, Din S, Gude NA, Collins B, V?lkers M, Thuerauf DJ, Glembotski CC, Chen CH, Lu KP, M?ller OJ, Uchida T, Sussman MA. Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1. Circ Res. 2013 Apr 26;112(9):1244-52. Chen CH, Chang CC, Lee TH, Luo M, Huang P, Liao PH, Wei S, Li FA, Chen RH, Zhou XZ, Shih HM, Lu KP. SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer Res. 2013 Jul 1;73(13):3951-62.-97 Rajbhandari P, Finn G, Solodin NM, Singarapu KK, Sahu SC, Markley JL, Kadunc KJ, Ellison-Zelski SJ, Kariagina A, Haslam SZ, Lu KP, Alarid ET. Regulation of estrogen receptor ± N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol Cell Biol. 2012 Jan;32(2):445-57. Ma SL, Pastorino L, Zhou XZ, Lu KP. Prolyl isomerase Pin1 promotes amyloid precursor protein (APP) turnover by inhibiting glycogen synthase kinase-32 (GSK32) activity: novel mechanism for Pin1 to protect against Alzheimer disease. J Biol Chem. 2012 Mar 2;287(10):6969-73.