Phenotypic Changes Underlying Visceral Hypersensitivity in a Mouse Model of IBs

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DESCRIPTION (provided by applicant): Visceral pain is currently the leading cause for patient visits in the U.S. In most gastrointestinal diseases, pain is often the first warning of organ dysfunction; however, in functional bowel disorders (FBD), like irritable bowel syndrome (IBS), pain is the main debilitating aspect of the condition. I have developed a mouse model of neonatal colon irritation (NCI) that reproduces the principal characteristic of IBS - colon hypersensitivity in the absence of histopathology. I hypothesize that early insult within the viscerosensory system results in long-lasting alterations in nociceptive processing at the level of the colon, peripheral nerve and DRG. To test this hypothesis I will employ three different physiological assays (a teased fiber preparation, calcium imaging and intracellular recordings from intact colon sensory neurons) along with anatomical analysis to determine how NCI results in visceral hypersensitivity. By understanding the underlying mechanisms of hypersensitivity in this model, I will lay the foundation for my future research program to study how changes in visceral sensory neurons contribute to, and/or may even cause, FBD. My training to date has resulted in multiple publications on sensory neuron plasticity that have relied heavily on anatomical techniques. However, to more fully address the role of neuronal dysfunction in FBD, I need to obtain the skills necessary to conduct physiological analysis of visceral neurons. The current environment at the University of Pittsburgh provides an excellent opportunity to obtain these technical skills due to the Pittsburgh Center for Pain Research, the associated research in the Division of Gastroenterology, and ongoing collaborations between basic science and clinical visceral pain investigators. Professional skills development will also be supported by the Office of Academic Career Development, the Center for Neuroscience at the University of Pittsburgh and my Mentoring Committee consisting of translational scientists working on various aspects of visceral pain. By furthering my technical and professional career development I will complete my transition into an independent academic researcher. Relevance: Approximately 15% of the general public suffers from Irritable Bowel Syndrome (IBS), of which the defining characteristic is intractable chronic pain. The proposed study uses a mouse model of IBS to identify the source and mechanism(s) of this chronic pain so that future experiments will be able to design novel therapies that will provide significant relief.