Generation and characterization of a humanized bradykinin B1 receptor mouse
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J. Fred Hess
Abstract
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.
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©2006 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Exploring the future of local vascular and inflammatory mediators
- Genetically altered animal models in the kallikrein-kinin system
- The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy
- Cross-talk of the renin-angiotensin and kallikrein-kinin systems
- Which endothelium-derived factors are really important in humans?
- Kinin- and angiotensin-converting enzyme (ACE) inhibitor-mediated nitric oxide production in endothelial cells
- Anti-inflammatory effects of kinins via microglia in the central nervous system
- Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma
- Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins
- Dual antagonists of the bradykinin B1 and B2 receptors based on a postulated common pharmacophore from existing non-peptide antagonists
- Generation and characterization of a humanized bradykinin B1 receptor mouse
- The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP)
- Molecular identification and pharmacological profile of the bovine kinin B1 receptor
- Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR)
- Cathepsin B localizes to plasma membrane caveolae of differentiating myoblasts and is secreted in an active form at physiological pH
Articles in the same Issue
- Exploring the future of local vascular and inflammatory mediators
- Genetically altered animal models in the kallikrein-kinin system
- The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy
- Cross-talk of the renin-angiotensin and kallikrein-kinin systems
- Which endothelium-derived factors are really important in humans?
- Kinin- and angiotensin-converting enzyme (ACE) inhibitor-mediated nitric oxide production in endothelial cells
- Anti-inflammatory effects of kinins via microglia in the central nervous system
- Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma
- Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins
- Dual antagonists of the bradykinin B1 and B2 receptors based on a postulated common pharmacophore from existing non-peptide antagonists
- Generation and characterization of a humanized bradykinin B1 receptor mouse
- The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP)
- Molecular identification and pharmacological profile of the bovine kinin B1 receptor
- Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR)
- Cathepsin B localizes to plasma membrane caveolae of differentiating myoblasts and is secreted in an active form at physiological pH
