Epithelial and Neuronal Interactions in Colitis: A Role for Sensory Neurons in Protecting the Colon Epithelium
Abstract
This proposal addresses Inflammatory Bowel Disease (IBD), a topic area selected for the fiscal year 2016 Peer Reviewed Medical Research Program. More than one million Americans suffer from IBD, which includes both Crohn s disease and ulcerative colitis. IBD is a chronic, painful disease characterized by symptoms including abdominal pain, diarrhea, weight loss, and fatigue. Equally important are the social and psychological impacts of IBD. Patients report negative impacts of IBD on career, daily activities, social interactions, relationships, and overall psychological well-being. Higher rates of depression are also observed among IBD patients. Currently, there is no cure for IBD, and long-term IBD remission is rare. It has been estimated, for example, that 75% of Crohn s disease patients experience a relapsing disease course and only 10% of Crohn s disease patients achieve long-term disease remission. As a chronic disease with a low mortality and a generally early age of onset, the prevalence of IBD is predicted to continue to grow over the next decade. With respect to the US military and Veteran populations, IBD prevalence between 2008-2009 was estimated to be 700 per 100,000 Department of Veterans Affairs users and 437 per 100,000 adult TRICARE users. Moreover, examination of IBD prevalence among Veterans between 1998-2009 revealed an increase of two- to three-fold over this period, paralleling increases in IBD prevalence observed in the civilian population. Thus, IBD is a significant health concern for both military and civilian US populations that will continue to drive healthcare costs higher. There is a great unmet need to understand the mechanisms driving IBD, with the ultimate goal of developing therapies to manage IBD symptoms, to promote IBD remission, and hopefully to cure IBD. It is known that sensory nerves in the colon transmit pain in response to IBD and that these sensory nerves can produce substances that can affect immune cells to worsen IBD. What has been much less appreciated, however, is the possibility that sensory neurons and their secreted products can directly affect the function of the epithelial cells lining the colon to provide protection against damage during IBD. The central hypothesis of this proposal is that sensory neurons function to protect the colon epithelium during IBD. The proposed studies will determine whether a specific channel present on many colon sensory neurons, known as the Transient Receptor Potential Ankyrin-repeat 1 channel (TRPA1), acts to protect colon epithelial cells during IBD. These studies will also determine whether sensory-neuron secreted Calcitonin-gene related peptide (CGRP) acts directly on colon epithelial cells to mediate protection. The goal of these studies is to determine how communication between sensory neurons and epithelial cells in the colon during IBD leads to protection of the epithelium. The role of sensory neurons in protecting colon epithelial cells in IBD is a little studied but potentially very important aspect of IBD. The novel idea that sensory neurons function in an epithelial protective pathway highlights a potential dual role for sensory neurons in IBD, with one being pain-inducing and the other being epithelial cell protecting. It is essential to elucidate the complex role of sensory neurons in IBD especially with drugs in development that completely inhibit sensory neurons to combat pain. A potential unintended consequence could be that while blocking pain, epithelial damage worsens as the protection pathway is simultaneously blocked. By understanding how the colon s nerves and epithelium communicate, it may be possible to identify new approaches for IBD treatments to improve the lives of the more than one million Americans, including military personnel, suffering from IBD. Only when both the pain and protection aspects of nerve function are fully understood will it be possible to develop drugs to lessen pain wi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710117
Entities
People
- Michele Battle
Organizations
- Medical College of Wisconsin
- United States Army