Faculty Profile

Address:
701 West 168th Street
Room 1212
New York, NY 10032

Phone: 212-305-6407

cws4@columbia.edu

Affiliations
Department of Microbiology
Department of Medicine
Herbert Irving Comprehensive Cancer Center
Flow Cytometry Facility

Collaborations
Cytokine Signaling and Immunology
Innate Immunity
Host Pathogenesis
STAT Structural Studies
Murine atherosclerosis/macrophage biology
Murine asthma

Training Activities
Immunology Training Program, Training Program in Immunological Disease Mechanisms
Integrated Program in Cellular, Molecular & Biophysical Studies
Graduate Program in Microbiology
MD/PhD Program
Cancer Training Program, Cell, Molecular and Developmental Biology of Cancer
Endocrinology Training Program, Hormones: Biochemistry and Molecular Biology
Clinical Endocrinology Training Program, Training Program in Endocrinology and Metabolism

Research Summary
Role of the JAK-STAT pathway in cytokine signal transduction.

Dr. Schindler's Laboratory

Characterization of the ability of one subfamily of hematopoietins, the Interferons (IFNs), to rapidly induce new genes led to the identification of the JAK-STAT signaling pathway. JAKs are receptor associated tyrosine kinases and STATs (Signal Transducers and Activators of Transcription) are the transcription factors they activate. Subsequent studies identified additional STATs in both mammals and lower eukaryotes.

Currently, the major interests in the laboratory include IFN signal transduction, Stat3 dependent responses and development of a better molecular understanding of STATs function. The laboratory also exploits mice deficient in their response to hematopoietins (e.g., STAT and receptor knockouts) to study their role in animal models of asthma and atherosclerosis.

IFN Studies - With the development of Stat2 knockout mice it has become possible to explore the role type I IFNs play in regulating immune response. The recent identification of plasmacytoid dendiritic cells (pDCs) as a major IFN-I secreting cell during infection has focused interest in understanding the role type I IFNs play in regulating the interface between innate and adaptive immunity.

Stat3 Studies - In contrast to the other mammalian STATs, Stat3 has been implicated in both development and tumorigenesis. One are of interest has been to develop methods to manipulate Stat3 activity in vivo to facilitate analysis of its role in development and immune response. Another effort has been on identifying proteins that interact with Stat3, like Stat Interacting Protein 1 (StIP1). Biochemical and genetic studies are underway to determine how StIP1 regulates Stat3 function.

STAT structure/function studies - Biochemical, structural and genetic approaches are being taken to characterize the structural changes that STATs undergo and determine how they regulate the nucleo-cytoplasmic distribution of STATs. Current efforts are directed at understanding how these modifications are carried out and how they regulate STAT function.

Atherosclerosis and Asthma Studies - Localization of T-cells and macrophages to atherosclerotic lesions suggests that cytokines and STATs contribute to atherogenesis. Current efforts are directed at developing mice in which it is possible to regulate the activity of macrophages in vivo. In addition, our expertise in cytokine signaling has led to collaborative studies through a recently NIH designated Columbia University Asthma Center to understand how exuberant allergic immune responses leads to the development of asthma. These studies exploit murine models of asthma.

Selected Publications

1. Braunstein, J., Brutsaert, S., Olson, R., Leung, C.,. and Schindler, C. (2003) STATs dimerize in the absence of phosphorylation. J. Biol. Chem., In press.

2. Battacharya, S. & Schindler, C. (2003) Regulation of Stat3 nuclear export. J. Clin. Invest. 111, 553-559.

3. Schindler, C. (2002) JAK-STAT signaling in human disease. J. Clin. Invest. 109, 1133-1137.

4. Kisseleva, T., Bhattacharya, S., Schröder-Braunstein, J., Schindler, C. (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1-24.

5. Song, L., Leung, C., Schindler, C. (2001). Lymphocytes are important in atherosclerosis. J. Clin. Invest., 108, 251-259.

6. Park, C., Li, S., Cha, E., Schindler, C. (2000) Immune response in Stat2 knock-out mice. Immunity 13, 795-804.

Current Projects

1. The Role of IL-3, IL-5 and GM-CSF in Asthma
We plan to study how the four-bundle-helix and StIP1 regulate STAT activity and determine the significance of signal decay on the biological response transduced by Stat5. Specifically we propose to: 1. Further characterize StIP1. 2. Functionally characterize the STAT four-bundle-helix. 3. Explore the role of Stat5 signal decay in primary leukocytes.
National Heart. Lung, and Blood Institute
7/2001-6/2005

2. Intervention of IL-5 Signaling: A Therapeutic Paradigm for Asthma
Burroughs Wellcome Clinical Scientist Award in Translational Research
7/1998-6/2003

3. STATs and their target genes mediate the potent biological response to interferons
Antonis Koromilas, P.I.; Christian Schindler, Project Leader
Human Frontier Science Program
9/2000-3/2004

4. IFN-a/b Signaling in the Treatment of Multiple Sclerosis
National Multiple Sclerosis Society
4/2001-3/2004

5. Columbia University Asthma Center; STAT Signaling in Dendritic Cells during Asthma
NIH
9/2001-8/2006

Recently Completed Funding/Projects

1. The Biochemical Genetics of Stat2 in IFN Signaling
NIH
7/1996-6/2001

2. The Role Interferon-g and Lymphocytes in Atherosclerosis
The Arterial Wall and Atherogenesis in Mice and Humans (SCOR)
NIH
4/1997-3/2002

Honors and Awards

Committees, Council Memberships

Keywords

asthma, biological signal transduction, colony stimulating factor, interleukin 3, interleukin 5, molecular pathology, transcription factor, binding protein, leukocyte, protein structure function, laboratory mouse, tissue /cell culture, transgenic animal

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