INK and NF-kappaB are involved in T-cell activation/differentiation, inflammatory responses, apoptosis, and cell proliferation. Protein phosphatase 4 (PP4) is an okadaic acid-sensitive protein serine/threonine phosphatase. To date, little is known about the functions of PP4. Our results provide the first evidence for the existence of PP4/JNK and PP4/ NF-kappaB modules as a new paradigm for the control of the signaling pathways in T cells. Understanding the underlying mechanisms of PP4-mediated T-cell signal transduction will lead to the discovery of the functions of PP4. This application plans to study the roles of PP4 in T-cell signaling and T-cell mediated immune responses. To unveil novel physiological functions of PP4 in T cells, we will generate PP4 knockout cells and mice using the Cre-foxP recombination system and Lck-Cre transgenic mice. The approaches are: (i) to understand the roles PP4 in T-cell proliferation, apoptosis, differentiation, centrosome function, and signaling using various biochemical and genetic approaches, and (ii) to study the in vivo functions of PP4 in Th1/Th2 differentiation, immune responses, and autoirnmunity. Ultimately, we plan to dissect various PP4-mediated signaling pathways in immune responses, leukemia/lymphoma, and immunological diseases. Our future understanding of host factors involved in the PP4-mediated lymphocyte signaling pathways will provide information fundamental to the discovery, design, and evaluation of effective intracellular therapeutic agents for leukemia/lymphoma, infections, and immunological disorders such as autoimmunity.
The specific aims are:
Aim 1. Study the roles of PP4 in T-cell proliferation, apoptosis, differentiation, and signaling using PP4 conditional knockout mice and cells.
Aim 2. Study in vivo functions of PP4 in T-cell mediated immune responses and autoimmunity using Tcell specific PP4 conditional knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066895-04
Application #
7408064
Study Section
Special Emphasis Panel (ZRG1-IMM-B (03))
Program Officer
Mallia, Conrad M
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$348,812
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030