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The Sundrud Laboratory

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Amino acid-responsive signaling and selective immunoregulation

Diagram of Chang Shan, Halofuginone and amino acid starvation Amino acids are essential building blocks used for protein synthesis. However, additional roles for amino acids have emerged in the regulation of eukaryotic signal transduction pathways. Eukaryotic cells use a network of signaling pathways to read-out and respond to minor fluctuations in amino acid availability, either through sensing free amino acid concentrations directly or through monitoring the state of tRNA charging. Amino acid restriction thus regulates cell signaling and cell behavior well before reaching levels that are limiting for basal cell activity or are cytotoxic. We have discovered that pathways activated by uncharged tRNA molecules, known collectively as the amino acid starvation response (AAR), specifically block the development and function of inflammatory T helper-17 cells (Sundrud et al., Science 2009).

Currently, we are exploring the mechanism by which the AAR modulates T cell development and function. We are using chemical biology approaches and mouse genetics to map amino acid-responsive pathways in T cells, with the aim of identifying novel targets and small molecules that can selectively regulate inflammation in clinical settings of autoimmune and malignant diseases, without inducing general immune suppression.

Identifying T cell subsets in clinical inflammation

Photo of a healthy and diseased stomach 
Current understanding of T cell lineages (e.g., Th1, Th2, Th17, Th22) is based largely on in vitro culture systems and the behavior of T cells in young mice housed in pathogen-free conditions. Not surprisingly, these insights fail to predict the phenotype and function of most endogenous human T cell populations, particularly those observed in clinical settings of inflammation. We have developed translational systems that allow us to explore the diversity of human T cells directly in autoimmune target organs, and have identified novel human T cell subsets not readily apparent in mice at steady-state. We are characterizing the function of these novel subsets both in vitro and in vivo, using mouse models of inflammation. These approaches allow for a clinically-grounded and unbiased evaluation of T cell lineages, and strengthen the therapeutic implications of downstream molecular characterization.

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