The Transgenic/Knockout Mouse Core provides a critical means by which the PPG will achieve its goal of understanding the in vivo functions of the TIM gene family. The Core has the expertise with both conventional and conditional transgenic and knockout technology that will enable the generation of novel mouse strains for analyzing the functions of TIM molecules in vivo. The core will be jointly managed by Drs Estelle Bettelli and Arlene Sharpe, who have extensive experience in generating transgenic and knock-out mice. Dr. Bettelli was instrumental in generating many of the TcR transgenic mice including MOG TcR transgenic mouse (2D2) and in addition in collaboration with Dr. Mohamed Oukka (PI. Core B), generated Fox-P3.GFP knock-in mice. Dr. Arlene Sharpe is a world leader in generating knock-out mice has thus far generated over two dozen knock-out mice including mice deficient in costimulatory and TIM molecules. Together, Dr. Bettelli and Dr. Sharpe will generate and provide many of the mouse strains deficient in TIM molecules to various projects.
Our specific aims are: 1) To generate transgenic strains that overexpress TIM genes, either constitutively or inducibly;the generation of transgenic mice that over-express TIM 3 will be our initial focus. 2) To generate novel mouse strains lacking TIM family members;the generation of TIM 3 deficient mice and TIM1/TIM 2 double deficient mice will be our initial focus. 3) To generate novel mouse strains that facilitate the analysis of the TIM gene function by breeding TIM transgenic or TIM deficient mice with cytokine reporter mice;the generation of TIM 3""""""""'"""""""" x IL-17, TIM 3""""""""'"""""""" x IL-10 and TIM 3""""""""'"""""""" x FoxPS reporter strains will be our initial focus. 4) To maintain and provide mice of existing transgenic, """"""""knock-out"""""""" and congenic strains to PPG investigators These studies will not only provide insights into the roles of TIM family members in regulating T cell activation and tolerance in vivo, but also may provide information critical for therapeutic manipulation of these key immunoregulatory molecules.
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