Post-transcriptional regulation in T cells

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

PROJECT SUMMARY T cell activation underlies the pathogenesis of many inflammatory disorders, including diseases of autoimmune and alloreactive background. Currently, many patients undergoing immunosuppressive therapy do not show a durable response, and are often refractory to second and third-line treatments. The identification of new targetable T cell signaling pathways may therefore pave the way for improved long-term treatment of inflammatory disease. Upon encountering their cognate antigen, T cells initiate a coordinated activation program involving changes in gene expression, epigenetics and protein synthesis to mount a rapid response, many of which are therapeutically targetable. Another critical mechanism for T cell regulation involves post- transcriptional control, including RNA processing and stability. We have identified an RNA-binding protein (RBP) that is induced following TCR activation, which exhibits previously uncharacterized roles in the post- transcriptional regulation of T cells. T cells deficient in this RBP showed defects in mRNA translation, as well as proliferation and differentiation. The goals of this research proposal are to investigate the role of this RBP in T cell-driven inflammatory disease using Graft-versus-Host Disease (GvHD) as a model (Aim 1), and elucidate the mechanistic basis for how this RBP post-transcriptionally regulates T cells (Aim 2). This project provides a unique opportunity for me to 1) gain expertise in an in vivo model of inflammatory disease (i.e. GvHD), 2) gain proficiency in computational analyses of high-throughput sequencing data of immune cells, and 3) form clinical and research mentorships tailored to my career goal of becoming a physician-scientist studying immune tolerance. This fellowship will allow me to create an early research niche within the field of immune tolerance which will be critical for my long-term objective to improve outcomes for patients with inflammatory disease.