(Ref. No. 342-JC)
p21-activated kinases (Paks) are Cdc42/Rac-activated serine–threonine protein kinases that regulate multiple key cancer-relevant signaling pathways. As over-expression or activation of Paks is frequently detected in various tumors, Paks have been proposed as potential oncogenic drivers in different human cancers. Genetic or pharmacological inactivation of Paks show reduced proliferation of different cancer cells in vitro and in vivo, which lead to the increased interest in developing Pak inhibitors as anti-cancer therapeutics. Adequate mouse models for testing potential Pak inhibitors are in great demand on the market.
Summary of the Invention
Researchers at Fox Chase Cancer Center have developed a unique transgenic mice line with targeted p21- Activated Kinase Inhibitor Domain (PID) designed to enable conditional expression of the PID in any cell, tissue, or organ of interest. In these transgenic mice, PID is inactive due to the PID sequence preceded by a stop cassette flanked by LoxP sites that are the binding sites of the recombinase Cre. When crossed with mice carrying a Cre transgene, the resulting Cre/PID mice express PID, which leads to inactivation of all group A Pak isoforms. Furthermore, the expression of PID can be controlled temporally and spatially by crossing the PID mice with either a mouse strain that carries a drug inducible Cre, or with a mouse strain that carries the Cre transgene under a tissue specific promoter. Thus, the PID transgenic mouse is a versatile in vivo model for investigating the role of group A Paks.
Applications of the Invention
As the p21-Activated Kinase Inhibitor Domain Targeted Mouse Model allows Paks to be conditionally inhibited in any elected tissue, our technology provides more reliable testing system for small molecule inhibitors in comparison to knock-out or shRNA-expressing mice, because the endogenous Pak proteins are still expressed, but the kinase activity is inhibited. The mouse model is also a powerful tool for evaluation of the role of group A Paks in normal mouse development and organ function, as well as in mouse disease models such as of cancer, neurologic diseases, including Fragile X syndrome and Alzheimer’s, and pathologic inflammatory states.
Patent Status: US 15/600,004 pending
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