Regulation of NFAT by the Rho GEF, GEF-H1

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DESCRIPTION (provided by applicant): T cells are necessary for defense against infections. Their role is to detect antigens that signal infection and mount an appropriate response. Activation begins with the signaling pathways from the T cell receptor (TCR) to a suite of transcription factors that induce the production of new genes, tuning the response to the specific invasion. NFAT is a transcription factor necessary for cell survival, proliferation, and effector function upon TCR stimulation. Its activation is markedly reduced in elderly populations, which leads to reduced efficacy of vaccinations in protecting against infection, and an increased risk of those infections without a preventative vaccine. A screen was performed for unknown activators of the NFAT pathway, and identified GEF-H1. Additional experiments revealed that GEF-H1is required for TCR signaling to NFAT. The goal of the outlined research is to show how GEF-H1 functions in the pathway. A strategy composed of three aims has been devised. Initially, steps in the TCR-to-NFAT pathway will be assayed in cells lacking GEF-H1 to determine what level in the pathway GEF-H1 acts. Next, the necessity of each domain in GEF-H1 will be tested for the restoration of NFAT activation in the GEF-H1 deficient cells. Finally, the role of the GEF-H1 target, RhoA, will be tested in the TCR pathway to NFAT. This research will expand our understanding of the regulation of T cells, and identify potential targets for the development of therapeutics to enhance sub-optimal immune responses seen in elderly patients. PUBLIC HEALTH RELEVANCE: As we age our immune system becomes less effective. This research would expand our knowledge of how a healthy immune response works, so that we may develop targeted strategies for enhancing the sub-optimal responses seen in elderly patients.