Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia, defined as an involuntary weight loss >5%, is present in up to 80% of these patients and it encompasses the loss of muscle and fat mass. Cachexia also contributes to a decrease in functional performance, quality of life and survival. However, treatments for this condition are lacking. Ghrelin, a novel hormone released primarily by the stomach stimulates GH secretion, increases energy intake and decreases energy expenditure. More recently it has been postulated to have anti-inflammatory actions. In our model of cachexia, administration of ghrelin induced an increase in lean body mass (LBM) and fat mass. However, its mechanisms of action in this setting are not fully understood. The long-term objective of this research is to determine the extent to which ghrelin improves cachexia and to establish the mechanisms mediating ghrelin's action in muscle and adipose tissue in this setting. Our hypotheses are that in the setting of cancer- and cisplatin-induced cachexia, ghrelin will prevent muscle wasting by downregulating proteolysis through the ubiquitin-proteasome pathway. These changes will be mediated through: a) increases in energy intake, b) activation of insulin-like growth factor-1 (IGF-1)-dependent pathways and c) downregulation of nuclear factor kappa B (NF:B)-dependent inflammatory pathways. We also hypothesize that ghrelin will prevent fat loss by decreasing lipolysis and by favoring fat storage. These changes will be mediated through: a) increasing food intake, b) decreasing energy expenditure and c) downregulating NF:B-dependent inflammatory pathways.
The specific aims are to: 1) Establish the mechanisms mediating ghrelin-induced muscle preservation in the setting of cisplatin-induced cachexia;2) Determine the mechanisms involved in ghrelin-induced fat deposition in the setting of cisplatin-induced cachexia;and 3) Characterize the effects of ghrelin in a tumor model of cachexia induced by the Lewis lung carcinoma (LLC) cell line. Research Design and Methods: In our rodent model of cisplatin-induced cachexia we have observed that ghrelin prevents cisplatin-induced fat and muscle atrophy. We are now proposing to determine the mechanisms involved in this setting and further characterize these pathways by using a different model of cachexia induced by LLC cell line. We will determine the role of endogenous ghrelin and the ghrelin receptor GHSR-1a by setting up our model of cachexia in ghrelin and GHSR1a knock-outs. We will establish the role of NF:B and inflammation by exploiting a new transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF:B consensus binding sites. The role of NF:B will be confirmed by using NF:B antagonists. The extent to which food intake regulates the pathways controlling fat and muscle mass will be established by performing pair-feeding experiments. The relative contribution of GH/IGF-1 activation to ghrelin's action will be tested by the administration of IGF-1 and GH receptor antagonists. Energy expenditure measurements will be performed by indirect calorimetry. Based on the data generated in our current model, we also will test the hypothesis that the same mechanisms are implicated in the setting of LLC tumor -induced cachexia. Taken together, these experiments will determine the mechanisms mediating ghrelin's protective effects in the setting of fat and muscle wasting related to cancer, addressing a clinical need and filling a void in the literature.
7. PROJECT NARRATIVE Cancer will affect 1 in 2 veterans and involuntary weight loss (also known as cachexia) resulting from a loss of fat and muscle mass will affect the vast majority of these patients. Cachexia often reduces functionality leading to a decrease in quality of life, poor response to anti-cancer therapies and increased mortality. Currently there is no effective way to treat cachexia. The novel hormone ghrelin increases appetite and body weight. This proposal will determine its effects and mechanisms of action in muscle and fat in the setting of cachexia. The results generated by this proposal will help us to develop treatments for cachexia, improving quality of life. By increasing muscle mass and function, patients will tolerate more effective treatments. They also will be able to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions.
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