Abstract

Clostridium difficile is the most common agent causing hospital-acquired diarrhea and colitis. It is now established that the peptide substance P (SP) is a critical mediator of the intestinal secretion and inflammation mediated by C. difficile toxin A. Two cell types that participate in the acute secretory and inflammatory responses to this toxin are the intestinal epithelial cells and intestinal macrophages. Functional substance P receptors (SPR) are markedly increased in both these cells within minutes of Clostridium difficile toxin A exposure and before secretory and inflammatory changes to this toxin are evident. Moreover, SPR in intestinal macrophages are functionally linked to the release of the proinflammatory cytokine TNFalpha and SP itself. The overall goal of this renewal application is to study the function and regulation of SPR in both these cells types.
In aim 1 we will study the mechanism(s) of SPR upregulation on purified intestinal epithelial cells during toxin A enteritis and determine the effects of inflammatory mediators and substance P itself on expression of these receptors. The signal transduction pathways that lead to expression of substance P receptors in response to substance P will also be examined.
In aim 2 we will examine whether proinflammatory cytokines can stimulate release of substance P from dorsal root, myenteric, and submucosal ganglia.
In aim 3 we will examine if inflammatory cytokines are involved in increased expression of SP binding sites in purified intestinal macrophages and determine the mechanism of this upregulation.
In aim 4 we will determine the pathophysiologic importance of SP receptors in activation of mast cells and intestinal macrophages in vivo using SP (NK-1) receptor deficient mice. All these studies will help understand the mechanism of SP receptor regulation during C. difficile toxin A- mediated acute intestinal secretion and inflammation and may lead to novel approaches for the treatment of intestinal inflammation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK047343-05A2
Application #
2843544
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1994-09-15
Project End
2003-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Beth Israel Medical Center (New York)
Department
Type
DUNS #
075255364
City
New York
State
NY
Country
United States
Zip Code
10003

  Publications

Hoffman, Jill M; Sideri, Aristea; Ruiz, Jonathan J et al. (2018) Mesenteric Adipose-derived Stromal Cells From Crohn's Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis. Cell Mol Gastroenterol Hepatol 6:1-16
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
Henström, Maria; Diekmann, Lena; Bonfiglio, Ferdinando et al. (2018) Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut 67:263-270
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
Mashaghi, Alireza; Marmalidou, Anna; Tehrani, Mohsen et al. (2016) Neuropeptide substance P and the immune response. Cell Mol Life Sci 73:4249-4264
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-133? expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 6:22195
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
Sideri, Aristea; Stavrakis, Dimitris; Bowe, Collin et al. (2015) Effects of obesity on severity of colitis and cytokine expression in mouse mesenteric fat. Potential role of adiponectin receptor 1. Am J Physiol Gastrointest Liver Physiol 308:G591-604
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

Showing the most recent 10 out of 67 publications