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Christian W. Schindler, M.D., Ph.D.
Associate Professor of Microbiology and Medicine
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Research
Summary
Role of the JAK-STAT pathway in cytokine signal transduction.
CURRENT RESEARCH:
2007 represents the 50th anniversary of the discovery of Interferon (IFN) research. The ensuing characterization of IFNs potent antiviral activity has punctuated a number of notable milestones in molecular immunology, including elucidation of the JAK-STAT signaling pathway. In this signaling paradigm, JAKs are receptor associated tyrosine kinases and STATs (Signal Transducers and Activators of Transcription) the transcription factors they activate. Subsequent studies have identified 7 STATs and 4 JAKs, providing important insight into how the ~50 members of the four-helix bundle cytokine family transduce their potent biological responses. This includes the regulation of several developmental pathways, as well as the innate and adaptive limbs of the immune system.
Interests in the laboratory include, understanding the critical role IFNs play in regulating innate immunity, Stat3’s intriguing development activity and the role the innate immune system plays in the development of chronic inflammatory disease, like atherosclerosis.
IFNs: Type I IFNs (IFN-Is; e.g., IFN-alpha), widely recognized for their antiviral activity (innate immunity), signal through Stat1 and Stat2, whereas type II IFN (i.e., IFN-gamma) signals exclusively through Stat1. Exploiting STAT and IFN receptor knockout mice has provided an opportunity to explore how IFNs regulate immunity. Recent studies have highlighted the critical role IFN-Is play in the innate response to bacterial, as well as viral pathogens. These studies have identified a sophisticated set of innate pattern recognition receptors (PRR) that recognize specific pathogen associated molecular patterns (PAMPs), culminating in the secretion of IFN-Is, as well as other inflammatory cytokines. An important effort in the laboratory entails exploring how the large IFN-I family (includes ~20 members) direct distinct biological responses, including an effective innate response to Legionella pneumophila, the causative agent of Legionnaires' Disease.
Stat3: In contrast to the other mammalian STATs, Stat3 has been highly conserved throughout evolution and implicated in the development and homeostasis of several cell lineages. Currently, tissues specific and conditional Stat3 gene targeting strategies are being exploited to understand the role Stat3 plays in immune homeostasis and tumorigenesis.
Atherosclerosis: The localization of immune cells to atherosclerotic lesions provided the first evidence that this pathology represented an aberrant immune response. Subsequent genetic studies, including several from our laboratory, have served to implicate IFN-g, but neither IL-6 nor lymphocytes in this process. Rather, the development of atherosclerotic lesions appears to arise from the chronic recruitment and activation of macrophages. Currently, the laboratory is focused on developing genetic models to study the complex relationship between cholesterol, innate immunity and macrophages in the pathogenesis of these debilitating lesions.
http://www.cumc.columbia.edu/dept/microbiology/faculty/schindler.html
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Selected Publications:
1. Schindler, C., Shuai, K., Prezioso, V., Darnell, JE. (1992) Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science
257,:809-813
2. Gupta, S., Pablo, AM., Jiang, X-c., Wang, N., Tall. AR., Schindler C. (1997) IFN-gamma potentiates atherosclerosis in apoE knock-out mice. J. Clin. Invest.
99:2752-2761
3. Azam, M., Lee, C., Strehlow, I., Schindler C. (1997) Functional distinct isoforms of Stat5 are generated by protein processing Immunity
6:691-701
4. Strehlow, I. and Schindler C. (1998) Amino terminal STAT domains regulate nuclear translocation and STAT deactivation. J. Biol. Chem.
273:28049-28056
5. Collum, B., Brutsaert, S., Lee, G., and Schindler C. (2000) A Stat3 Interacting Protein (StIP1) Regulates Cytokine Signal Transduction. Proc. Natl. Acad. Sci., USA
97:10120-10125
6. Park, C., Li, S., Cha, E., Schindler, C. (2000) Immune response in Stat2 knock-out mice Immunity
13:795-804
7. Song, L., Leung, C., Schindler, C. (2001) Lymphocytes are important in atherosclerosis. J. Clin. Invest.
108:251-259
8. Kisseleva, T., Song, L., Vorontchikhina, M., Feirt, N., Kitajewski, J., Schindler, C. (2006) NFkB regulation of endothelial cell function during LPS toxemia and cancer. J. Clin. Invest.
116:2955-2963
9. Song, L., Battacharya, S., Yunis, AA., Lima, CD., Schindler, C. (2006) SUMO modification of Stat1. Blood
108:3237-3244
10. Schindler, C., Levy, DE., Decker, T. (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem
282:20059-20063
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