Summary: Neurotransmitters do more than cause muscles to contract and glands to secrete, they play an important role in modifying the activity of the immune system. Inflammatory bowel diseases (IBD) are caused by overactive immune responses, so dampening the immune system is an important means of treating IBD. A branch of the nervous system, the sympathetic nervous system (SNS), participates in the regulation of the gastrointestinal tract and can modulate intestinal inflammation. Therefore, the SNS potentially has the ability to suppress inflammation during IBD. A recent study in an animal model of IBD reported that a drug which targets a receptor for a sympathetic neurotransmitter can decrease disease severity. However, we have found that IBD inhibits the release of this neurotransmitter, which limits the ability of these receptors to suppress inflammation. Therefore, this grant proposes to use a mouse model of IBD to examine how inflammation inhibits sympathetic neurotransmitter access to its receptors and how the immune system is modulated by the SNS. Where possible, findings in the mouse model will be confirmed by studying human tissue from biopsies of IBD patients and normal patients undergoing routine surveillance screening for colon cancer. By examining the reciprocal interactions between the immune system and the SNS, we hope to develop strategies to enhance the immunosuppressive actions of the SNS in IBD patients.