Knockout Mouse Model
A genetically engineered mouse in which a specific gene has been inactivated (knocked out) to study the gene's function. Knockout models are used to understand the biological roles of peptide receptors and signalling pathways targeted by therapeutic compounds.
Technical Context
CRISPR/Cas9 and earlier technologies (homologous recombination in ES cells) enable targeted gene deletion. Knockout models relevant to peptide pharmacology include: GLP-1 receptor knockout (GLP-1R-/-) mice (used to confirm GLP-1R-dependent effects of GLP-1 RAs — effects abolished in KO mice confirm on-target activity), MC4R knockout mice (develop obesity, modelling MC4R-deficiency obesity targeted by setmelanotide), GHSR knockout mice (resistant to ghrelin's GH-stimulating and orexigenic effects), and various neuropeptide receptor knockouts (elucidating the physiological roles of individual neuropeptide systems). Conditional knockouts (gene deletion in specific tissues or at specific developmental stages using Cre-lox technology) enable more nuanced analysis. Phenotyping of knockout animals reveals the physiological role of the deleted gene/receptor system.