Understanding the impact of AAK1 on T cell chemokine receptor expression and chemotaxis

PROJECT SUMMARY/ABSTRACT T cells infiltrating into the brain directly and indirectly promote neuronal impairment in a wide variety of neuroinflammatory diseases, including dementia, multiple sclerosis (MS), and epilepsy. Thus, limiting T cell infiltration into the central nervous system could have therapeutic benefit for these patients. Adapter protein 2 associated kinase 1 (Aak1) was recently identified as an important regulator of T cell chemotaxis into inflamed tissues in an in vivo forward genetic screen. The primary objective of this project is to understand how AAK1 regulates T cell chemotaxis, with a secondary goal of establishing the translational potential of AAK1 as a therapeutic target in neuroinflammatory diseases. These goals will be accomplished in two aims. Aim 1 will determine if AAK1 regulates chemokine receptor expression on the T cell surface using primary T cells. Aim 2 will define the extent to which AAK1 regulates T cell chemotaxis using in vitro migration assays and in vivo T cell trafficking into the brain using the Theiler’s murine encephalomyelitis virus (TMEV) model of MS. This proposal has several innovative aspects, including generation of a novel, T cell specific Aak1 knockout mouse, validation of Aak1 as a genetic regulator of T cell infiltration, functional and mechanistic testing of a novel Aak1 mutant construct, and evaluation of Aak1 as a novel therapeutic target to limit T cell chemotaxis into inflamed tissue. Successful completion of this project will broadly benefit many disease settings, as findings can easily be translated to other inflammatory conditions where recruitment of T cells drives pathogenicity and may lead to better treatments of immunologic diseases.