Ras genes are some of the best-studied genes in biomedical research due to their central role in mitogenic signaling and their oncogenic activation in one third of all human tumors. More recently, Ras genes have also been implicated in developmental disorders including Costello and Noonan syndromes. In spite of this wealth of information, we still do not know the role of Ras proteins in adult homeostasis and, more importantly, how their misregulation affects human health. The latter is of paramount importance in order to develop efficacious therapies against tumors carrying Ras oncogenes - an achievement that could save thousands of lives worldwide. We propose to address these issues using genetic approaches in mouse models. We aim to systemically ablate all Ras genes in adult mice as well as in selective tissues to understand their role in normal homeostasis. We also propose to characterize mouse models for developmental disorders induced by hyperactive Ras proteins. These models should help us to better understand these human disorders as well as tools to test potential therapeutic strategies. Finally, we propose to use K-Ras driven mouse tumor models for human PDA and NSCLC to address key questions that may be directly translated to the clinic. In the case of PDA, we propose to study the contribution of the inflammatory response induced by pancreatitis to tumor development. In the case of NCSLC, we propose to isolate cancer initiating cells in an attempt to reveal the earliest events in tumor development. Moreover, we intend to use this tumor model to validate druggable Ras downstream effectors as therapeutic targets. The results derived from these studies should provide key information to design forthcoming clinical trials that will benefit cancer patients.
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