The pathophysiology of Inflammatory Bowel Disease (IBD), a clinical entity with significant morbidity and mortality, is not completely understood. Emerging evidence indicates that neuropeptides are major participants in the pathogenesis of colonic inflammation. We showed that the neuropeptide neurotensin (NT) acts as a proinflammatory mediator in the acute phase of colitis. Our preliminary evidence also indicates that NT deficient mice have reduced intestinal inflammatory responses, providing direct evidence for the importance of this peptide in intestinal inflammation. However, NT also promotes healing during the repair phase of inflammation by activating the EGF receptor (EGFR) and phosphorylating the anti-apoptotic signaling molecule Akt. Thus, our hypothesis for aim 1 of this revised renewal application is that NT participates in the healing phase of colitis by reducing apoptosis and increasing cell proliferation.
Aim 1 therefore will examine the signaling mechanisms involved in NT-NT receptor 1 (NTR1)-induced Akt-and EGFR-related anti-apoptotic and proliferative responses in isolated colonocytes and models of experimental colitis. We also found increased NT and NTR1 expression in the mesenteric fat depots during colitis and identified expression of NT and NTR1 in mouse preadipocytes that respond to NT be release of cytokines and increased proliferation. These findings link for the first time NT-NTR1-dependent inflammatory changes in mesenteric fat during colitis and may be of major importance in IBD where fat wrapping of the bowel is a common finding during surgery of IBD patients. Thus, in aim 2 will examine the NT-mediated cross talk between the colonic mucosa and mesenteric depots in acute and chronic experimental colitis by comparing NT and NTR1 expression in mesenteric fat to the degree of mucosal and adipose tissue inflammation in IBD-related models. Experiments in isolated preadipocytes will examine the mechanisms by which NT stimulates release of proinflammatory cytokines and adipokines, alters expression of adhesion molecules, and stimulates macrophage migration to these cells. Experiments in aim 1 and 2 will also compare colitis and inflammatory changes in fat depots between NT deficient and wild type mice. Studies in aim 3 will determine the signal transduction pathways involved in NT-induced IGF-1R phosphorylation in preadipocytes and examine the mechanisms by which NT-NTR1 interactions lead to cell proliferation and migration. Our results will provide important insights on the role of NT and its receptor in colonic inflammation and its expanded role in activation and inflammation of mesenteric adipose tissue observed in IBD and animal models of experimental colitis. PUBLIC HEALTH REVELVANCE This project will examine the pathophysiologic mechanisms by which the neuropeptide neurotensin participates in the pathogenesis of intestinal inflammation and Inflammatory Bowel Disease. Part of this project also examines how this neuropeptide influences development of inflammation in the adjacent fat tissue following colonic inflammatory changes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Hamilton, Frank A
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Fang, Kai; Law, Ivy Ka Man; Padua, David et al. (2018) MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis. Am J Pathol 188:586-599
Law, Ivy Ka Man; Padua, David Miguel; Iliopoulos, Dimitrios et al. (2017) Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology. Am J Physiol Gastrointest Liver Physiol 313:G361-G372
Padua, David; Pothoulakis, Charalabos (2016) Novel approaches to treating Clostridium difficile-associated colitis. Expert Rev Gastroenterol Hepatol 10:193-204
Padua, David; Mahurkar-Joshi, Swapna; Law, Ivy Ka Man et al. (2016) A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation. Am J Physiol Gastrointest Liver Physiol 311:G446-57
Bakirtzi, Kyriaki; Law, Ivy Ka Man; Xue, Xiang et al. (2016) Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1?-miR-210 Signaling. J Immunol 196:4311-21
Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W et al. (2016) Neurotensin-induced miR-133? expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 6:22195
Sideri, Aristea; Bakirtzi, Kyriaki; Shih, David Q et al. (2015) Substance P mediates pro-inflammatory cytokine release form mesenteric adipocytes in Inflammatory Bowel Disease patients. Cell Mol Gastroenterol Hepatol 1:420-432
Law, Ivy Ka Man; Bakirtzi, Kyriaki; Polytarchou, Christos et al. (2015) Neurotensin--regulated miR-133? is involved in proinflammatory signalling in human colonic epithelial cells and in experimental colitis. Gut 64:1095-104
Koukos, Georgios; Polytarchou, Christos; Kaplan, Jess L et al. (2015) A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium. Inflamm Bowel Dis 21:996-1005
Polytarchou, Christos; Hommes, Daniel W; Palumbo, Tiziana et al. (2015) MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice. Gastroenterology 149:981-92.e11

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