The role of Mediator in T-bet-dependent gene activation and its dysregulation in mucosal inflammatory disease.

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Our immune system functions to protect us from infection and keep commensal microorganisms that live on and within our bodies in check. However, the immune system can also become dysregulated, instead damaging organs and tissues. This can cause chronic inflammatory diseases, which include Crohn's disease, ulcerative colitis and celiac disease, which primarily affect the bowel. These diseases cluster in families, suggesting a genetic component. Unfortunately, the number of people affected by these diseases is increasing and the treatment options that are currently available are poor. There are a number of components of the immune system. CD4 T cells secrete signals that help other cells control microorganism numbers. CD4 T cells are normally resting but when the cell detects a foreign object, the cell changes into one of a number of different types of effector cell, each of which activates a different component of the immune response. The type of effector cell it becomes depends on the type of foreign object detected and allows the immune response to tailor itself to different threats. It is also important that the appropriate balance between these different effector types is maintained because excessive activation can lead to inflammatory diseases.The differentiation of CD4 T cells into effector lineages is controlled by transcription factors, proteins that bind to specific sites on DNA and turn on and off near-by genes. Thus, if we could understand how these transcription factors function to turn on and off genes, and how this changes in disease, we might be able to develop drugs that modulate this process and block damaging immune responses.We have identified a set of proteins that are required by a transcription factor called T-bet to activate immune response genes. Blocking the activity of one of these proteins, Cdk9, reduced inflammation in a model of the inflammatory eye disease, uveitis. We have also found that genetic variants that are more often found in people with inflammatory bowel disease affect the ability of T-bet to bind to DNA. This suggests that these genetic variants increase disease risk because they obstruct how immune genes are normally turned on and off.The aim of this project is to determine how T-bet works with the proteins we have identified to turn immune genes on, to discover how the genetic variants associated with disease affect this process, and to test whether blocking the function of Cdk9 and other proteins in this pathway can reduce symptoms in models of inflammatory bowel disease.This work will increase our understanding of the normal process through which genes are turned on during an immune response, which will be important to support this process in people whose immune systems are not functioning well. This research will also reveal how the genetic variants present in some people cause dysregulation of the immune system and how this can increase the risk of those individuals developing inflammatory diseases. Finally, this work will identify a set of possible drug targets through which chronic inflammatory diseases might be treated in the future.