Communication between the endocrine and immune system is important in controlling the organism's response to inflammatory stimuli. Ghrelin, a newly identified potent growth hormone secretagogue, is a unique acylated 28 amino-acid peptide that is secreted predominantly from the stomach and enters the central nervous system where it stimulates growth hormone release from the pituitary. Ghrelin also increases appetite and food intake and stimulates obesity. Ghrelin and its receptor are expressed in stomach, small intestine, and colon of animals and humans as well as in endocrine tumors of the stomach and intestine. Ghrelin stimulates gastric acid secretion, and accelerates gastric emptying and small intestinal transit of a liquid meal. However, no information exists on whether ghrelin participates in the pathophysiology of systemic or intestinal inflammation. Our preliminary evidence indicates that expression of ghrelin and its receptor (GHS-R) gene is dramatically upregulated during 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced colonic inflammation, an animal model of Crohn's Disease. Moreover, using rat and human intestinal cells we show that binding of ghrelin to its receptor causes MAP kinase and NF-kappaB activation, and stimulates expression of interleukin-8, a potent chemotactic factor for neutrophils. These results open up the possibility that apart from its orexigenic and metabolic effects, ghrelin may play an important role in inflammatory processes. Our hypothesis is that peripheral ghrelin augments intestinal inflammation via binding to its specific receptors in the intestine and activation of the transcription factor kappaB. The overall goal of this proposal is to study the role of ghrelin and its receptor in the development of intestinal inflammation and identify the molecular mechanisms whereby these molecules participate in the inflammatory process.
In aim 1 we will characterize expression of ghrelin and its receptor in different models of intestinal inflammation, and identify the cells expressing these molecules in the intestinal mucosa.
Aim 2 will examine whether ghrelin and ghrelin receptor antagonism alter the development of intestinal inflammation in vivo. Experiments in aim 3 will determine the role of the NF-kappaB pathway in ghrelin-induced IL-8 gene expression and examine the upstream pathways involved in ghrelin-induced NF-kappaB activation. Understanding the role of ghrelin in intestinal inflammation and the molecular mechanisms whereby it stimulates expression of inflammatory cytokines such as IL-8, will provide important insights into the pathophysiology of human inflammatory bowel disease (IBD), and possibly other inflammatory conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Zhao, Dezheng; Desai, Sachin; Zeng, Huiyan (2011) VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: role in VEGF-induced angiogenesis. Int J Cancer 128:2602-12
Zhao, Dezheng; Bakirtzi, Kyriaki; Zhan, Yanai et al. (2011) Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells. J Biol Chem 286:6092-9
Zhao, Dezheng (2007) Protein kinase Cdelta-mediated CREB activation regulates ghrelin-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colonic epithelial cells. J Cell Biochem 102:1245-55
Zhao, Dezheng; Zhan, Yanai; Zeng, Huiyan et al. (2007) Neurotensin stimulates expression of early growth response gene-1 and EGF receptor through MAP kinase activation in human colonic epithelial cells. Int J Cancer 120:1652-6
Zhao, Dezheng; Zhan, Yanai; Zeng, Huiyan et al. (2006) Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-kappaB pathway in human colonic epithelial cells. J Cell Biochem 97:1317-27
Qin, Liuliang; Zeng, Huiyan; Zhao, Dezheng (2006) Requirement of protein kinase D tyrosine phosphorylation for VEGF-A165-induced angiogenesis through its interaction and regulation of phospholipase Cgamma phosphorylation. J Biol Chem 281:32550-8
Qin, Liuliang; Zhao, Dezheng; Liu, Xin et al. (2006) Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res 4:811-20
Zhao, Dezheng; Zhan, Yanai; Zeng, Huiyan et al. (2005) Neurotensin stimulates interleukin-8 expression through modulation of I kappa B alpha phosphorylation and p65 transcriptional activity: involvement of protein kinase C alpha. Mol Pharmacol 67:2025-31
Zhao, Dezheng; Zhan, Yanai; Koon, Hon Wai et al. (2004) Metalloproteinase-dependent transforming growth factor-alpha release mediates neurotensin-stimulated MAP kinase activation in human colonic epithelial cells. J Biol Chem 279:43547-54