T cell migration is a critical to both the initiation of the immune response as well as the effector phase of T cell function. While many of the cell surface molecules that drive T cell motility have been identified, relatively few intracellular signaling pathways have been investigated that contribute to normal T cell motility. In addition, as leukemic cells from T-acute lumphoblastic leukemia (T-ALL) use conserved pathways to mediate T-ALL migration, it is likely that T-ALL and normal T cells share common signaling components to mediate cell migration. The long term goal of this application is to identify novel signaling pathways that can control normal T cell and T-ALL cell migration. Our proposal seeks to define the mechanism by which these molecules regulate specific aspects of motility. The objective of this particular application is to define the mechanism by which PKC? regulates T cell migration. Based on our preliminary results showing that PKC? can regulate T cell migration, the central hypothesis of this proposal is that PKC? is a novel regulator of T cell and T-ALL migration. Understanding the role of PKC? and novel downstream effectors on T cell and T-ALL migration may provide new therapeutic targets for drug development to treat T-ALL and modulate T cell migration in autoimmune disorders. We will use mouse models to understand how PKC? and other signaling molecules affect T cell migration both in vitro and in vivo. We will also develop a xenograft mouse model of T-ALL migration to study the potential effect of PKC? on T-ALL. Our innovative proposal identifies previously unknown players that regulate the fundamental process of T cell migration. These studies will result in a significant advance in our understanding of the signaling molecules that control T cell and T-ALL cell migration, leading to the identification of novel targets for drug development to treat T-ALL.

Public Health Relevance

The proposed application is relevant to public health because identification of novel molecules that control T cell migration can lead to new targets for therapeutic development which can regulate movement of both normal and leukemic T cells. This study will not only develop fundamental knowledge regarding normal T cell behavior, it will also shed light on what molecules may regulate cancer cell migration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097202-02
Application #
8463453
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$354,850
Indirect Cost
$119,850
Name
University of New Mexico Health Sciences Center
Department
Genetics
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Fricke, G Matthew; Letendre, Kenneth A; Moses, Melanie E et al. (2016) Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search. PLoS Comput Biol 12:e1004818
Torres, David J; Cannon, Judy L; Ricoy, Ulises M et al. (2016) Self-Contained Statistical Analysis of Gene Sets. PLoS One 11:e0163918
Levin, Drew; Forrest, Stephanie; Banerjee, Soumya et al. (2016) A spatial model of the efficiency of T cell search in the influenza-infected lung. J Theor Biol 398:52-63
Letendre, Kenneth; Donnadieu, Emmanuel; Moses, Melanie E et al. (2015) Bringing statistics up to speed with data in analysis of lymphocyte motility. PLoS One 10:e0126333
Carroll-Portillo, Amanda; Cannon, Judy L; te Riet, Joost et al. (2015) Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation. J Cell Biol 210:851-64
Zhou, Hui-fang; Yan, Huimin; Cannon, Judy L et al. (2013) CD43-mediated IFN-γ production by CD8+ T cells promotes abdominal aortic aneurysm in mice. J Immunol 190:5078-85
Cannon, Judy L; Asperti-Boursin, Francois; Letendre, Kenneth A et al. (2013) PKCθ regulates T cell motility via ezrin-radixin-moesin localization to the uropod. PLoS One 8:e78940