Research Abstract:
My laboratory’s main interest is in identifying molecular mechanisms of lymphocyte activation and development. Using forward genetics, we have generated several lines of immunocompromised mice. With SNP analysis, these immunologic phenotypes are mapped to their causative genes for the purpose of discovering new genes or gene functions in the immune system.
In this manner, we have identified a mouse line that is deficient in ItpkB, a kinase that converts the Ca2+-regulating second messenger IP3 into IP4. Our studies demonstrate an independent role for IP4 as an important second messenger that is critical for lymphocyte development and activation. Using proteomics, we have identified many IP4 binding proteins that we are currently characterizing as putative IP4 effectors.
Disregulation of PIP3 levels can often lead to tumoriogenesis. Due to the structural similarity between PIP3 and IP4, we are exploring the potential of IP4 as a regulator of cellular transformation.
In a second mouse model, WeeT, we are genetically mapping the gene responsible for a different immunodeficiency. These mice have reduced peripheral T lymphocytes due to a migration defect from the thymus, where T cells develop. Detailed mechanistic analysis of these animals will provide insight into how lymphocytes traffic to survey the body for infections and antigenic challenge.
Selected Publications:
Fu G, Vallée S, Rybakin V, McGuire MV, Ampudia J, Brockmeyer C, Salek M, Fallen PR, Hoerter JAH, Munshi A, Huang YH, Hu J, Fox HS, Sauer K, Acuto O and Gascoigne NRJ. Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling. Nature Immunology 2009 10: 848-56.
Huang YH, Hoebe K and Sauer K. New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B. Expert Opin Ther Targets. 2008 12: 391-413.
Huang YH, Grasis JA, Miller AT, Xu R, Soonthornvacharin S, Andreotti AH, Tsoukas CD, Cooke MP and Sauer K. Positive Regulation of Itk PH Domain Function by Soluble IP4. Science 2007 316: 886-9
Miller AT, Sandberg M, Huang YH, Young M, Sutton S, Sauer K and Cooke MP. Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation. Nature Immunology 2007 8: 514-21.
Huang YH, Barouch-Bentov R, Herman A, Walker J and Sauer K. Integrating traditional and postgenomic approaches to investigate lymphocyte development and function. Advances in Experimental Medicine & Biology 2006 584: 245-76.
Last Updated: 08/12/2009 |