Proper regulation of the PI-3 kinase (PI3k) pathway is critical for normal T cell development, activation and homeostasis. Several negative regulators of this pathway have been extensively characterized, two of which are tumor suppressors. Recently, another negative regulator of the PI3k pathway has been identified. PIK3IP1 is a transmembrane protein that has the ability to bind the catalytic protein p110 and prevent its activation. Thus far, nothing is known about the possible role of PIK3IP1 in the regulation of lymphocyte development or activation. We have found that PIK3IP1 is expressed in T cells and that ectopic expression of PIK3IP1 inhibits TCR/CD28 signaling to inducible transcription. Conversely, siRNA- mediated silencing of pik3ip1 augments activation of the same pathways. These results suggest that the PI3k regulator PIK3IP1 plays an important role in T cell activation. We will therefore determine the effects of PIK3IP1 on specific signaling pathways downstream of the TCR and CD28, including the role of specific domains within PIK3IP1 for this activity. We will also examine the expression of PIK3IP1 message and protein throughout T cell development in normal mice. Finally, we will characterize an inducible knockout of PIK3IP1 lacking expression of the protein in the T cell lineage.

Public Health Relevance

Completion of this project will allow us to determine, for the first time, the role of the novel protein PIK3IP1 in T cell development and activation. These studies may open the door to further in vivo characterization of the function of this novel regulator of the PI3k pathway in normal and pathological aspects of T cell biology. Given what is known about the role of PI3k in human disease, this may include information relevant for the diagnosis or treatment of various cancers or autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI095730-02
Application #
8522148
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Mallia, Conrad M
Project Start
2012-08-03
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$215,201
Indirect Cost
$74,201
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213