Columbia University Health Sciences

Division of Pulmonary, Allergy & Critical Care

Divisional Research Activities

The Laboratory of Dr. Christian Schindler

The approximately 50 members of the hematopoietin family of cytokines regulate the development of numerous cellular lineages and immune response. They achieve this by binding to specific receptors and activating specific signaling pathways within target cells. These signals lead to the induction of new genes that are critical for the development of the ensuing biological response.

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. The more primitive STATs largely regulate developmental pathways. By contrast, in higher eukaryotes STATs have evolved to regulate blood lineages and their ability to promote immunity. Gene targeting studies have determined that each of the 7 mammalian STATs plays a pivotal role in transducing biological response and exhibits a remarkably degree of ligand specificity.

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. Details are provided in the four paragraphs.

IFN Studies - Type I IFNs (e.g., IFN-alpha's), widely recognized for their antiviral activity (innate immunity), signal through Stat1 and Stat2. Type II IFN (i.e., IFN-gamma) signals exclusively through Stat1. 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. Intriguingly, IFN secreting pDCs have also recently been implicated in the immune dysregulation associated with the development of Systemic Lupus, a debilitating human autoimmune disease.

Stat3 Studies - In contrast to the other mammalian STATs, Stat3 has been implicated in both development and tumorigenesis. Moreover, Stat3’s ability to down regulate immune response may contribute to its role in tumor growth. 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 - STATs undergo structural changes upon activation that renders these cytosolic proteins competent for nuclear translocation and DNA binding. Biochemical, structural and genetic approaches are being taken to characterize these changes and determine how they regulate the nucleo-cytoplasmic distribution of STATs. Recent studies have determined that covalent modifications of the STAT protein, including acetylation and SUMOylation, may also participate in the regulation of STAT nuclear localization. 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. Recent studies have implicated both IFN-? and IL-6 in lesion development. Current efforts are directed at developing mice in which it is possible to regulate the activity of macrophages in vivo. This will provide a unique opportunity to explore the important role macrophages play the development of atherosclerosis as well as other important disease. 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.