Testing the Role of p21-Activated Kinases in Schwannoma Formation Using a Novel Genetically Engineered Murine Model that Closely Phenocopies Human NF2 Disease
Abstract
The major goal of this research project was to genetically and pharmacologically test the requirement of Group A PAK signaling in Nf2 deficient schwannoma genesis. We planned to accomplish this goal by (1) using our genetically intercrossed Pak1, Pak2 and a dominant negative Group A PAK transgene with our PostnCre;Nf2flox/floxmouse schwannoma model in order to generate functional (ABR testing) and histological readouts. In turn these readouts will allow us to utilize a genetic approach to determine if indeed PAK signaling is essential to the development of Nf2-deficient schwannomas; (2) using histological and ABR readouts, we will treat PostnCre;Nf2flox/floxmice with three different pharmacologic PAK inhibitors to determine if targeted PAK inhibition in a preclinical model of schwannoma genesis rescues tumor development. We are on track to accomplish the goals we set. In the first year of the funded work, we completed crosses of Pak1-/- and Pak2flox/flox mice with PostnCre;Nf2flox/floxmice 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 are ongoing. We also began Aim 2, treating PostnCre;Nf2flox/floxmice with Pak small molecule inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2015
- Accession Number
- ADA621814
Entities
People
- Jonathan Chernoff