Childhood obesity is one of the major health threats for modern American society. A major concern regarding childhood obesity is that obese children face an increased risk of diabetes mellitus, hypertension, stroke and coronary artery diseases. Obesity is a particularly challenging medical condition to treat because of its multi-factorial etiology and existing therapeutic limitations. The melanocortin-4 receptor (MC4R) has been identified to play a key role in the regulation of food intake and body weight. Our long term goal is to elucidate the molecular basis of hMC4R responsible for ligand binding and signaling as a necessary prerequisite to the development of selective MC4R nonpeptide agonist for therapeutic treatment of obesity. We hypothesize that unique amino acid residues in the transmembrane domains of hMC4R are involved in the selective MC4R agonist binding. To test this hypothesis, we will utilize 1) novel photoaffinity labeling of selective agonist to examine the direct interaction between the ligand and MC4R, and 2) identify the direct interactions between selective agonist and MC4R using reciprocal ligand and receptor residue exchange. Our proposed studies will provide the finest level of molecular detail for ligand binding, receptor signaling and will provide valuable information for designing selective MC4R agonists that may be used in the treatment of human obesity. Obesity is one of the major health threats facing modern American society. This R03 application is to explore the molecular basis of melanocorin 4 receptor responsible for agonist activity which can be used to develop new therapuetic approach for obesity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD058789-01
Application #
7510184
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Huang, Terry T-K
Project Start
2008-08-07
Project End
2010-07-31
Budget Start
2008-08-07
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$72,500
Indirect Cost
Name
University of Alabama Birmingham
Department
Surgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Yang, Yingkui (2011) Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol 660:125-30
Yang, Yingkui; Cai, Minying; Chen, Min et al. (2009) Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling. Regul Pept 155:46-54
Yang, Yingkui; Hruby, Victor J; Chen, Min et al. (2009) Novel binding motif of ACTH analogues at the melanocortin receptors. Biochemistry 48:9775-84
Chen, Min; Cai, Minying; McPherson, David et al. (2009) Contribution of the transmembrane domain 6 of melanocortin-4 receptor to peptide [Pro5, DNal (2')8]-gamma-MSH selectivity. Biochem Pharmacol 77:114-24