Obesity is now a major health problem and even mild obesity enhances the risk of premature death, diabetes mellitus, hypertension, hyperlipidaemia, atherosclerosis, coronary heart disease, osteoarthritis, and certain types of cancer. The exact origins of obesity still remains cryptic, however, the combination of genetic factors, reduced activity and inappropriate eating are all thought to be major contributors to this problem. A recently identified key regulator of feeding behavior is ghrelin, a unique amino octanoic acid serine acylated peptide that is an endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is synthesized principally in the stomach and appears to function as a feedback signal of energy insufficiency that is released during fasting or substantial weight loss. Its anabolic function appears to be important in terms of obesity and, in particular, the failure of treatments to sustain weight loss. Positive correlations are seen in the increase in serum ghrelin levels with the degree of weight loss attained during treatment. This counter-regulatory action of ghrelin to prevent the consolidation of greater weight loss could be addressed with the development of suitable ghrelin functional antagonists. We propose to address this problem through the following specific aims: 1) The preparation of human single chain antibodies (scFv) that can specifically bind both human and/or rat ghrelin. 2) The conversion of these scFvs to full-length IgG molecules. 3) The construction of phagemid vectors that contain the genes of selected human scFvs specific for ghrelin; the preparation of these phage particles in large quantities. 4) The characterization in vivo of the anorectic activity/specificity of both IgG and phage-displayed anti-ghrelin antibodies in the rat. The use of these protein based therapeutics that specifically sequester ghrelin within the periphery and/or the CNS before reaching its target receptor(s) could prove to be a valuable approach for controlling food intake with the context of dietary-induced obesity and potentially the devastating consequences of future associated diseases. ? ? ?
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