The long-term goal of the work described in this competitive renewal application is to understand how Notch1 functions in T cell development and differentiation in order to develop new approaches for manipulating Notch signaling in the immune system, cancer and other Notch-related pathologies. Notch1 is one of four evolutionarily conserved Notch receptors that mediate intercellular signals to regulate cell differentiation, growth and survival in a variety of cell types. Notch1 signals are required to induce T cell specification from a multipotent progenitor in the thymus and are then required during early stages of T cell development required to direct expression of the pre-T cell receptor on the developing T cell. Notch is no longer essential in subsequent thymic T cell differentiation, however, in the periphery, Notch signaling is essential for the proper differentiation of helper Type 2 cells. As a transmembrane receptor that ultimately acts as a transcriptional activator in the nucleus, the primary function of Notch in T cell development and differentiation is to activate transcription. Although some direct Notch targets have been identified in developing and differentiating T cells, this has not been done at a genome level and the precise mechanisms by which Notch regulates transcription in T cell development and differentiation are poorly understood. Using antibodies that we raised against Notch1, we will use a genome wide approach to describe the direct targets of Notch activation and the mechanism by which Notch functions to activate these targets. We will use this information to identify the location of Notch binding sites, other transcription factors that Notch """"""""speaks to"""""""", and identify novel mechanisms of Notch transcriptional activation and repression. One unique aspect of Notch transcriptional regulation recently described by us is that dimeric Notch transcriptional complexes exert important functions in T cell development. We will use multiple approaches to identify dimeric Notch transcriptional targets and identify how they function in T cell development and differentiation. We will also determine the effect of inhibiting Notch dimerization on murine development and homeostasis.
Notch signaling is an important regulator of T cell development and function, whose dysregulation can lead to cancer and other defects. The precise role exerted by Notch at different stages of differentiation is context and dose-dependent, and we have developed methodologies to interrogate the mechanism by which Notch regulates different transcriptional programs at diverse stages of differentiation. Understanding the precise mechanism by which Notch regulates T cell development and differentiation will lead to new therapeutic strategies for cancer and other Notch-influenced diseases.
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