Much has been learned in recent years regarding the biochemical events most critical for signal transduction mediated by numerous cell surface receptors on immune cells. A key second messenger is diacylglycerol (DAG), which is formed when engaged ITAM-bearing receptors activate the phosphatidylinositol cascade. DAG, in turn, stimulates at least two critical signaling cascades; the Ras pathway and several protein kinase C family members. Thus, understanding the formation of DAG and its metabolism is key to understanding immune cell activation. One means by which DAG function is terminated is the conversion of DAG to phosphatidic acid by DAG kinases (DGKs). This proposal focuses on DGKzeta, one of two DGKs expressed at high levels in hematopoietic cells. Our preliminary data indicate that DGKzeta is an important in vivo negative regulator of T cell and mast cell function. The experiments described in this proposal will make use of cell lines and genetically altered mice to investigate how DGKzeta serves this key role.
Three specific aims will be pursued. First, we propose a cell biologic and biochemical analysis of DGKzeta to determine its subcellular localization and features most critical for affecting signaling pathways.
The second aim will investigate the impact of DGKzeta deficiency on in vivo T cell function and the third aim will examine similar questions in the mast cell compartment.
Both aims 2 and 3 will extend the structure/function analysis to determine features of this enzyme most essential for responses to immunologic challenges. We anticipate that this work will shed additional light on the complex regulation of T cell and mast cell function and will hopefully suggest novel approaches to modulate activity of these cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058019-02
Application #
6845716
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Mallia, Conrad M
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$396,250
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zou, Tao; Caton, Andrew J; Koretzky, Gary A et al. (2010) Dendritic cells induce regulatory T cell proliferation through antigen-dependent and -independent interactions. J Immunol 185:2790-9
Juntilla, Marisa M; Koretzky, Gary A (2008) Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol Lett 116:104-10
Olenchock, Benjamin A; Guo, Rishu; Carpenter, Jeffery H et al. (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol 7:1174-81