The long-range goal of this project is to define the mechanism of phosphoinositide 3-kinase (PI3K) signaling in lymphocytes. As PI3K is required for lymphocyte proliferation, advances in this area may lead to novel strategies for the treatment of immunodeficiency, autoimmunity, transplant rejection and cancer. The central hypothesis guiding this application is that the PI3K regulatory isoforms p85alpha and p85beta have distinct functional roles in lymphocyte signaling. To test this hypothesis, this investigator?s laboratory has generated mice lacking either p85alpha or p85beta. p85alpha-deficient mice exhibit B cell defects similar to those seen in mice lacking Btk, BLNK or PLCgamma2. These findings support a model that PI3K activation is important for membrane assembly of a signaling complex that facilitates PLCgamma2 activation and sustained calcium flux. T cells and B cells rely on distinct proteins to carry out many of the signaling steps that link the antigen receptor to calcium flux and proliferation. For example, calcium flux in T cells is regulated by Itk, a functional homolog of Btk. Preliminary results suggest that p85beta may be an important PI3K regulatory isoform in T cell signaling. This application has three specific aims:
Aim 1 is to test the model that p85alpha is required for activation of Btk and PLCgamma2 leading to sustained Ca2+ flux. Biochemical assays will be used to analyze signaling in primary B cells and immortalized B cell lines lacking p85alpha.
Aim 2 is determine if p85beta is required for T cell proliferation and cytokine production.
Aim 3 is to determine whether p85beta is required for activation of Itk, PLCgamma1, and sustained Ca2+ flux in T cells. Biochemical assays will be used to analyze signaling in purified T cells. These studies will increase our understanding of PI3K signaling, a central control point in lymphocyte proliferation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050831-04
Application #
6837137
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mallia, Conrad M
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
4
Fiscal Year
2005
Total Cost
$342,860
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Mouta-Bellum, Carla; Kirov, Aleksander; Miceli-Libby, Laura et al. (2009) Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha. Dev Dyn 238:2670-9
Alcázar, Isabela; Cortés, Isabel; Zaballos, Angel et al. (2009) p85beta phosphoinositide 3-kinase regulates CD28 coreceptor function. Blood 113:3198-208
Oak, Jean S; Chen, Jing; Peralta, Raechel Q et al. (2009) The p85beta regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells. Autoimmunity 42:447-58
de Souza, Anjali J; Oak, Jean S; Jordanhazy, Ryan et al. (2008) T cell Ig and mucin domain-1-mediated T cell activation requires recruitment and activation of phosphoinositide 3-kinase. J Immunol 180:6518-26
Kharas, Michael G; Janes, Matthew R; Scarfone, Vanessa M et al. (2008) Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest 118:3038-50
Deane, Jonathan A; Kharas, Michael G; Oak, Jean S et al. (2007) T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling. Blood 109:2894-902
Kharas, Michael G; Yusuf, Isharat; Scarfone, Vanessa M et al. (2007) KLF4 suppresses transformation of pre-B cells by ABL oncogenes. Blood 109:747-55
Oak, Jean S; Fruman, David A (2007) Role of phosphoinositide 3-kinase signaling in autoimmunity. Autoimmunity 40:433-41
Donahue, Amber C; Fruman, David A (2007) Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli. Eur J Immunol 37:2923-36
Matheu, Melanie P; Deane, Jonathan A; Parker, Ian et al. (2007) Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J Immunol 179:2261-9

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