In an effort to identify factors responsible for the maintenance of the anergic phenotype we employed a novel statistical algorithm, HAM (Hypothesis based Analysis of Microarrays) to interrogate a data base consisting of T cell stimulated under conditions that either promote full T cell activation or anergy. Among the genes identified by this approach was Sprouty 1 a member of an evolutionarily conserved family of inducible inhibitors that has been mostly studied in the field of Development. In particular Sprouty 1 has been implicated in negative feedback loops that impart spatial temporal constraints to intracellular signals. In this project we will dissect the mechanism by which Sprouty 1 inhibits T cell activation and maintains the anergic state.
In Aim I we will determine the mechanisms governing the expression of Sprouty 1 and the precise biochemical mechanisms by which Sprouty 1 inhibits TCR-induced signaling.
In Aim II, in collaboration with Project 2, we will determine how the structure and intracellular trafficking of Sprouty 1 dictates its inhibitory function.
In Aim III using conditional Sprouty 1 null mice we will determine the role of Sprouty 1 in regulating viral, """"""""self and tumor immune responses in vivo. Overall dissecting the mechanisms by which Sprouty 1 inhibits T cell function should provide important insight in terms of identifying novel pharmacologic targets. For example in autoimmune diseases and transplantation, the goal would be to inhibit T cell activation but leave Sprouty 1 signaling intact. Alternatively, for tumor immunity, developing strategies to inhibit Sprouty 1 function and thus enhance the anti-tumor response.
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