Generation and characterization of a humanized bradykinin B1 receptor mouse.
Antagonists of the B1 bradykinin receptor (B1R), encoded by the BDKRB1 gene, offer the promise of novel therapeutic agents for inflammatory and neuropathic pain. However, the in vivo characterization of the pharmacodynamics of B1R antagonists is hindered by the low level of B1R expression in healthy tissue and the profound species selectivity exhibited by many compounds for the B1R. To circumvent these issues we generated two genetically engineered rodent models. The first is a transgenic rat over-expressing the human B1R under the control of the neuronal-specific enolase promoter; we previously reported the utility of this model in assessing human B1R receptor occupancy in the central nervous system of the rat. The second model, reported here, utilized gene-targeting by homologous recombination to replace the genomic coding sequence for the endogenous mouse B1R with that of the human B1R. The mRNA expression profile of the humanized Bdkrb1 (hBkdrb1) allele is similar to that of the mouse Bdkrb1 (mBkdrb1) in the wild-type animal. Furthermore, in vitro assays indicate that tissues isolated from the humanized mouse possess pharmacological properties characteristic of the human B1R. Therefore, we have generated a humanized B1R mouse model that is suitable for testing the efficacy of human B1R-selective compounds.
Department of Neuroscience Drug Discovery, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA. fred_hess@merck.com
J Fred
JF
Hess
Richard Z
RZ
Chen
Patricia
P
Hey
Robert
R
Breese
Ray S L
RS
Chang
Tsing-Bau
TB
Chen
Mark G
MG
Bock
Thomas
T
Vogt
Douglas J
DJ
Pettibone
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D015394:Molecular Structure; D012333:RNA, Messenger / Q000235:genetics; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000502:physiology; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic
D000081:Acetamides; D065169:Bradykinin B1 Receptor Antagonists; C511495:N-(2-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethyl)-2-(3-oxo-1-(1,2,3,4-tetrahydroquinolin-8-ylsulfonyl)piperazin-2-yl)acetamide; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D013450:Sulfones