Pancreas development requires different signaling processes and the concerted activities of various transcription factors. Remarkably, some of the key molecular components of pancreatic diseases are also critical regulators during normal pancreas organogenesis. Thus, unraveling the intricate molecular machinery regulating mammalian pancreas development is necessary not only to understand the origins of pancreatic dysfunction, but also to develop tools for better treatment and prevention of pancreatic diseases. Our initial studies on Prox1 identified this transcription factor as a crucial, novel regulator of multiple processes during early pancreas organogenesis. First and foremost, our studies showed that in developing pancreatic tissues the activity of Prox1 enables epithelial growth and morphogenesis. In addition, Prox1 appears to be a crucial component of a genetic program that is destined to produce the cellular complexity of the mammalian pancreas (Wang et al., 2005). Unfortunately, our previous studies could not determine how the lack of Prox1 activity affects overall pancreas organogenesis, how this deficiency affects pancreatic function, or whether Prox1 activity is necessary in ? cells to maintain blood glucose homeostasis, because Prox1-nullizygous embryos die in utero. In order to answer these important questions, in this proposal we put forward several experimental approaches to uncover the molecular mechanism of Prox1 function in developing pancreatic tissues of mice, to investigate how the loss of Prox1 function affects pancreas homeostasis at postnatal stages;and to determine if Prox1 function is required for ? cell function. After concluding the experimental approaches outlined in this proposal I expect to have uncovered important, novel functions of Prox1 in pancreatic tissues of embryos or adults;to obtain valuable information on the cellular and molecular mechanisms controlled by Prox1 in developing pancreatic tissues;and to generate several novel strains of mice that could be valuable to the scientific community for future studies. The ultimate goal of our research is to contribute to disclose the molecular origin of human pancreatic diseases, and to develop novel therapies to overcome those diseases.
