The long-term objective of this proposal is to understand how the immune and neuroendocrine systems interact when activated by an inflammatory stimulus.
The Specific Aims will focus on the inflammatory cytokines and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation, and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which is synthesized by fat cells and plays a key role in regulating energy homeostasis, can also modulate the inflammatory response. Alpha-MSH which is derived from the proopiomelanocortin (POMC) precursor protein, is synthesized in the periphery and can be regulated by leptin. Alpha-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of alpha-MSH, the melanocortin receptors, and the MSH antagonist, agouti-related protein (AGRP), in modulating cytokine and neuroendocrine responses. This proposal will examine the role of leptin, alpha-MSH and AGRP in modulating pro-inflammatory (IL-1-beta, IL-6, TNF-alpha) and anti-inflammatory cytokine (1L-1-beta and IL-10) responses to endotoxin and IL-1-beta in the rhesus monkey. Major goals will be to determine the physiological roles that alpha-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by alpha-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and to examine the effects of leptin on IL-1-beta stimulated CRH release from the hypothalamus in vitro. Mice which overexpress alpha-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin. Inflammatory cytokines have been implicated in a wide spectrum of human diseases ranging from infectious and autoimmune diseases to osteoporosis and cardiovascular disease. Within the brain, inflammatory cytokines have been implicated in neurodegenerative disease and illness-associated depression. An understanding of the endogenous hormonal mechanisms which regulate this inflammatory cytokine cascade is thus relevant to a broad range of human diseases ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH055708-05A1
Application #
6577628
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Winsky, Lois M
Project Start
1998-03-10
Project End
2007-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$408,750
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Lee, Michelle; Kim, Andrea; Conwell, Irene M et al. (2008) Effects of selective modulation of the central melanocortin-3-receptor on food intake and hypothalamic POMC expression. Peptides 29:440-7
Lee, Michelle; Kim, Andrea; Chua Jr, Streamson C et al. (2007) Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am J Physiol Endocrinol Metab 293:E121-31
Lee, Michelle; Wardlaw, Sharon L (2007) The central melanocortin system and the regulation of energy balance. Front Biosci 12:3994-4010
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2006) Melanocortin modulation of inflammatory cytokine and neuroendocrine responses to endotoxin in the monkey. Endocrinology 147:1878-83
Landman, Rita E; Puder, Jardena J; Xiao, Ennian et al. (2003) Endotoxin stimulates leptin in the human and nonhuman primate. J Clin Endocrinol Metab 88:1285-91
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate. Endocrinology 144:4350-3
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate. Endocrinology 144:1736-41
Puder, J J; Freda, P U; Goland, R S et al. (2001) Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab 86:2403-8
Wardlaw, S L (2001) Clinical review 127: Obesity as a neuroendocrine disease: lessons to be learned from proopiomelanocortin and melanocortin receptor mutations in mice and men. J Clin Endocrinol Metab 86:1442-6
Xiao, E; Xia-Zhang, L; Ferin, M et al. (2001) Differential effects of estradiol on the adrenocorticotropin responses to interleukin-6 and interleukin-1 in the monkey. Endocrinology 142:2736-41

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