As part of our studies to elucidate the mechanism of action of BRS-3 agonists, we have preliminary data that BRS-3 agonists increase metabolic rate via stimulating brown adipose tissue. These studies are being confirmed and expanded upon. We are also investigating the role fo BRS-3 in blood pressure control. In order to study the specific cells, sites, tissues, and transmitters by which BRS-3 acts, we are generating the following tools: 1) a conditional knockout floxed Brs3 mouse, 2) a knockin mouse with Cre recombinase driven by Brs3, and 3) a BAC transgenic mouse with Brs3 driving GFP expression. The long-term investment required to generate and validate these tools is expected to yield great rewards in future years. We are collaborating with Merck, using selective BRS-3 compounds (particularly the agonists MK-5046 and MK-7255). Additionally, work on BRS-3 that I was involved with at Merck Research Laboratories prior to my arrival at NIDDK continues to be guided through to publication.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$336,109
Indirect Cost
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State
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Xiao, Cuiying; Reitman, Marc L (2016) Bombesin-Like Receptor 3: Physiology of a Functional Orphan. Trends Endocrinol Metab 27:603-5
Lateef, Dalya M; Xiao, Cuiying; Brychta, Robert J et al. (2016) Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310:H891-8
Lateef, Dalya M; Xiao, Cuiying; Reitman, Marc L (2015) Search for an Endogenous Bombesin-Like Receptor 3 (BRS-3) Ligand Using Parabiotic Mice. PLoS One 10:e0142637
Lateef, Dalya M; Abreu-Vieira, Gustavo; Xiao, Cuiying et al. (2014) Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3. Am J Physiol Endocrinol Metab 306:E681-7
Hatoum, Ida J; Greenawalt, Danielle M; Cotsapas, Chris et al. (2013) Weight loss after gastric bypass is associated with a variant at 15q26.1. Am J Hum Genet 92:827-34
Moreno, Paola; Mantey, Samuel A; Nuche-Berenguer, Bernardo et al. (2013) Comparative pharmacology of bombesin receptor subtype-3, nonpeptide agonist MK-5046, a universal peptide agonist, and peptide antagonist Bantag-1 for human bombesin receptors. J Pharmacol Exp Ther 347:100-16
Reitman, Marc L (2013) FGF21 mimetic shows therapeutic promise. Cell Metab 18:307-9
Chobanian, Harry R; Guo, Yan; Liu, Ping et al. (2012) The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization. Bioorg Med Chem 20:2845-9
Reitman, Marc L; Dishy, Victor; Moreau, Allison et al. (2012) Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients. J Clin Pharmacol 52:1306-16
Guan, Xiao-Ming; Metzger, Joseph M; Yang, Liming et al. (2011) Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist. J Pharmacol Exp Ther 336:356-64

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