Our results show that the peptide neurotensin (NT) and its high affinity receptor (NTR1) play a critical role in the pathophysiology of both colonic inflammation and colon cancer by activating expression of proinflammatory, proliferative and anti-apoptotic genes. Gene expression is negatively regulated by microRNAs, leading to mRNA degradation, and/or inhibition of translation into protein. MiRs are also important regulators of Inflammatory Bowel Disease (IBD). We recently reported that NT/NTR1 interactions in human colonocytes differentially regulate expression of microRNAs that affect colon tumorigenesis through stimulation of miRNA feedback networks involving inflammatory and anti-apoptotic pathways. This is the first evidence in the literature supporting the notion that neuropeptides modulate micorRNA expression in colonic epithelial cells and that this interaction is functionally correlated with modulation of a GI disease. Here we will test the novel hypothesis that the NTR1 - regulated microRNAs miR-210 and miR-133a play an important role in the pathophysiology of IBD-like colitis by activating pathways linked to inflammatory signaling and NTR1 internalization. The following aims will address these hypotheses.
Aim 1 will determine the importance of miR- 210 in NT-associated proinflammatory responses in human colonic epithelial cells and examine the upstream and downstream signaling pathways involved in this response.
Aim 2 will assess the importance of miR-133a in NTR1 trafficking and its role as a link of proinflammatory responses to receptor trafficking in human colonic epithelial cells and study the mechanisms eliciting this response. Use of human disease samples will confirm the IBD relevance of the findings in aims 1 and 2.
Aim 3 will determine the functional significance of the relationship of NT and NTR1 to miRNAs-210 and 133a in models of colitis. Studies in this aim include use of NT, and NTR1 deficient mice in models of colitis that will help verify NT-associated miR-210-driven signaling targets and angiogenesis and NT-linked miR-133a-associated receptor trafficking. These studies should advance our understanding on the pathogenesis of IBD and define the role and mechanisms of NTR1- microRNA signaling in this group of diseases.

Public Health Relevance

Inflammatory Bowel Disease (IBD) is one of the major illnesses in the gastrointestinal tract associated with several fatal complications and accelerated incidence in the United States over the past 60 years. Findings from the proposed studies should advance our understanding on the mechanism(s) underlying IBD and define the mechanism of participation of the neuropeptide neurotensin and its receptor in the pathophysiology of intestinal inflammation of this important and common group of diseases. Results from our studies may form the basis for novel specific therapeutic approaches to combat intestinal inflammation that may have a significant impact, not only in the GI inflammation field, but also in the general field of neuropeptide receptor signaling and inflammation in other organs.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK060729-12
Application #
8737224
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bakirtzi, Kyriaki; Law, Ivy Ka Man; Xue, Xiang et al. (2016) Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling. J Immunol 196:4311-21
Padua, David; Pothoulakis, Charalabos (2016) Novel approaches to treating Clostridium difficile-associated colitis. Expert Rev Gastroenterol Hepatol 10:193-204
Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W et al. (2016) Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 6:22195
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
Fang, Kai; Sideri, Aristea; Law, Ivy Ka Man et al. (2015) Identification of a novel substance P (SP)-neurokinin-1 receptor (NK-1R) microRNA-221-5p inflammatory network in human colonic epithelial cells. Cell Mol Gastroenterol Hepatol 1:503-515
Law, Ivy Ka Man; Pothoulakis, Charalabos (2015) MicroRNA-133α regulates neurotensin-associated colonic inflammation in colonic epithelial cells and experimental colitis. RNA Dis 2:
Law, Ivy Ka Man; Bakirtzi, Kyriaki; Polytarchou, Christos et al. (2015) Neurotensin--regulated miR-133α 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
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
Bakirtzi, Kyriaki; West, Gail; Fiocchi, Claudio et al. (2014) The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. Am J Pathol 184:3405-14

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