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Testing the Role of p21 Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease


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The major goal of this research project was to genetically and pharmacologically test the requirement of PAK signaling in Nf2 deficient schwannoma genesis. We planned to accomplish this goal by (1) using genetically intercrossed Pak1, Pak2 and a dominant negative Group A PAK transgene with our PostnCre;Nf2flox/flox mouse schwannoma model in order to generate functional (ABR testing) and histological readouts. These readouts allow us to utilize a genetic approach to determine if PAK signaling is essential to the development of Nf2-deficient schwannomas; (2) using histological and ABR readouts, we will treat PostnCre;Nf2flox/flox mice with three different pharmacologic PAK inhibitors to determine if targeted PAK inhibition in a preclinical model of schwannoma genesis rescues tumor development. By the end of year two, we completed crosses of Pak1-/- and Pak2flox/flox mice with PostnCre;Nf2flox/flox mice and analyzed the effects of Pak loss on hearing and tumor growth. As we had speculated, loss of Pak1 function partly prevented hearing loss and tumor growth. Studies on Pak2 were also complete, and showed that loss of this kinase did not affect tumor growth. Treating these mice with Pak small molecule inhibitors was less successful, and we are currently attempting to determine the reasons why.



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