The presence of chronic inflammatory states is known to cause perturbations in the regulatory mechanisms that maintain the normal morphological and functional features of the gastric mucosa, leading to the development of diseases such as gastritis, peptic ulcer and gastric cancer. The factors involved in the pathogenesis of these conditions have been only partially characterized. The bone morphogenetic proteins, (BMP) s are regulatory peptides that exert important actions on the growth and differentiation of gastrointestinal tissues. In addition, the BMPs have been shown to exert anti-inflammatory actions in the gut, suggesting that they might represent novel and hitherto poorly characterized regulators of gastrointestinal inflammation. The mechanisms mediating the anti-inflammatory actions of the BMPs in the stomach are currently unknown. In a series of preliminary studies we observed that inflammatory stimuli such as Helicobacter pylori (Hp) and INF-3 induce the expression of BMP-4 both in vivo and in vitro, supporting the notion that BMP-4 is involved in the regulation of gastric inflammation. We also noted that transgenic expression of the BMP inhibitor noggin in the mouse stomach, leads to increased expression of cytokines, such as MIP-2, INF-3 and TNF-1, and to enhanced activation of kinases, such as the ERKs and the JNKs, which are involved in the regulation of pro- inflammatory mechanisms. The relevance of these findings was underscored by the observation that infection of the transgenic mice with Hp, leads to the development of greater inflammatory changes than in non- transgenic, age matched, littermates. Finally, in a series of in vitro studies, we noted that BMP-2, BMP-4 and BMP-7 exert direct, inhibitory actions on both basal and TNF-1-stimulated IL-8 gene expression in cultures of canine parietal and mucus cells. On the basis of these observations we hypothesize that the BMPs exert anti- inflammatory actions in the stomach and that lack of BMP signaling leads to the development of more dramatic and intense inflammatory changes. Accordingly, the overall goal of this application is to investigate the function and the mechanisms of actions of BMP signaling in the regulation of inflammatory mechanisms in the stomach, by using both in vivo and in vitro approaches. In the first specific aim we will test the hypothesis that inflammatory stimuli such as Hp, IFN-3 and TNF-1 regulate BMP expression in vivo and that this event might represent a self-safe mechanism that down-regulates the intensity of the inflammatory response. In the second aim, we will elucidate the role of BMP signaling in the regulation of the inflammatory response in vivo, by challenging the noggin transgenic mice with the inflammatory stimuli. In the third aim, we will focus on the actions of BMP signaling on the expression of IL-8 in cultures of isolated parietal and mucus cells. Through the proposed studies, we expect to shed new insights that will have significant implications in clinical medicine since our discoveries may contribute to a better understanding of the pathophysiology of diseases such as peptic ulcer and gastric cancer.

Public Health Relevance

Project Narrative Through the proposed studies, we hope to shed new insights that will have significant implications in clinical medicine since our findings may contribute to a better understanding of the pathophysiology of diseases such as peptic ulcer and gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083373-02
Application #
8251117
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$270,570
Indirect Cost
$96,570
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Takabayashi, Hidehiko; Shinohara, Masahiko; Mao, Maria et al. (2014) Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice. Gastroenterology 147:396-406.e7