The applicant for this Mentored Clinical Scientist Development Award is currently completing a Fellowship in Gastroenterology and Hepatology at the University of Pittsburgh Medical Center. During his training to obtain combined M.D. and Ph.D. degrees under the mentorship of Bruce Rabin, M.D., Ph.D., the candidate investigated extensively the neural and neuroendocrine mechanisms of stressor-induced immune alterations int he rat, focusing specifically on stress-activated CNS pathways that may modulate lymphocyte function. In these studies, the candidate identified stress-activated neurons in the rat CNS by using c-FOS expression as a marker of neuronal stimulation following acute footshock and conditioned stress. To further his career in academic medicine and to further develop his expertise in neuro-immune interactions and stress, the candidate has designed this research proposal to assess the roles of stress and intestinal inflammation in the development of visceral hyperalgesia in the gut. This model of colonic inflammation (trinitrobenzenesulfonic acid in ethanol) appears to be propagated by cells of the immune system and is subsequently modulated by stress. Understanding the pathophysiologic roles of these factors in the sensitization of gastrointestinal afferents will help further provide important information regarding the etiology and clinical course (including relapse) of painful bowel disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Methods encompassing intestinal electrophysiology, neuropharmacology, histology, and mast cell growth factors will be used to evaluate, in a hapten- induced model of colonic inflammation, the chemical dialog between afferent nerves and inflammatory/immune cells is likely to contribute to the sensitization of gastrointestinal afferents in pathological conditions such as IBS and IBD. This dialog may be modulated by activity in autonomic pathways to the gut and/or by chemicals released from the pituitary gland during stress. Combining these new skills with those previously acquired, the applicant will be well-suited to study a variety of gastrointestinal disease states in addition to characterization of the neuroimmune mechanisms of visceral hyperalgesia.
| Buchholz, Bettina M; Shapiro, Richard A; Vodovotz, Yoram et al. (2015) Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus. Am J Physiol Gastrointest Liver Physiol 308:G852-62 |
| Schmidt, Joachim; Stoffels, Burkhard; Chanthaphavong, R Savanh et al. (2012) Differential molecular and cellular immune mechanisms of postoperative and LPS-induced ileus in mice and rats. Cytokine 59:49-58 |
| Chang, Johannes; Wehner, Sven; Schäfer, Nico et al. (2012) Iatrogenic extracellular matrix disruption as a local trigger for postoperative ileus. J Surg Res 178:632-9 |
| Buchholz, B M; Chanthaphavong, R S; Billiar, T R et al. (2012) Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock. Neurogastroenterol Motil 24:658-69, e294 |
| Moore, Beverley A; Manthey, Carl L; Johnson, Dana L et al. (2011) Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative ileus. Gastroenterology 141:1283-92, 1292.e1-4 |
| Tsukamoto, T; Antonic, V; El Hajj, I I et al. (2011) Novel model of peripheral tissue trauma-induced inflammation and gastrointestinal dysmotility. Neurogastroenterol Motil 23:379-86, e164 |
| Stoffels, B; Türler, A; Schmidt, J et al. (2011) Anti-inflammatory role of glycine in reducing rodent postoperative inflammatory ileus. Neurogastroenterol Motil 23:76-87, e8 |
| Buchholz, B M; Bauer, A J (2010) Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis. Neurogastroenterol Motil 22:232-45 |
| Buchholz, Bettina M; Billiar, Timothy R; Bauer, Anthony J (2010) Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus. Am J Physiol Gastrointest Liver Physiol 299:G531-8 |
| Ustinova, Elena E; Fraser, Matthew O; Pezzone, Michael A (2010) Cross-talk and sensitization of bladder afferent nerves. Neurourol Urodyn 29:77-81 |
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