The NF Center: from Animal Models to Therapeutics OPERATIONAL PLAN FOR OVERALL CENTER This application arises in direct response to PA Number: PAR-04-018 for NATIONAL CENTERS FOR NEUROFIBROMATOSIS RESEARCH. In the elaboration of Proposed Research Projects (pages 2 &3 of the PA), the first four bullet statements were: ? Molecular and cell biological studies of NF1... ? Investigation of pathogenesis of neurofibromas, gliomas,... ? High throughput preclinical screening for candidate NF therapeutics. ? Development of improved cell and animal models for preclinical screening. The present application directly addresses these first bullet statements. Project 1 is entirely composed of proposed experiments to characterize and improve optic glioma mouse models as well as preexisting neurofibroma models. This extends previous modeling work performed in the Pi's laboratory. In addition, this proposal will examine gene expression profiles of the tumors and tumor cells arising in these models as a means of identifying novel therapeutic targets and testing them in cells. Projects 2 and 3 will explore cellular interactions between all of the cells that compose neurofibromas. They will identify relevant signaling intermediates in these cell-cell interactions and test therapeutic interventions to neutralize them. In addition they will use genetic strategies to test critical determinants of signaling in neurofibroma formation. Therefore, the proposed experiments are specifically directed to address critical themes requested by the PA. We view the evolution of this NF Center, which is currently a combination of basic research and cell and animal model based research to evermore become translational and aimed at clinical trials. Our explicit objective in all aims include the identification of critical signaling pathways in development of optic glioma and neurofibroma, the two most common tumors in NF1. The scientific work of this Neurofibromatosis Center will progress as if this were a single RO1 grant, only on a larger scale. Essentially, the Center will be carrying out a series of highly integrated studies aimed at addressing the causes and biological details of the two most common tumors found in Neurofibromatosis Type 1;neurofibromas and optic gliomas. The ultimate objective is to use these studies to identify therapeutic targets for treatment of these tumors. Each of the Projects focuses on related cellular and molecular constituents of NF1 associated tumors, and examines the complex cell interactions related to the cause of these tumors. The Transgenic Core and Imaging Core provide the tools that each Project needs to facilitate and enhance this research. Each Project and Core, therefore, can be seen as just one part of the overall effort to understand how NF1 partial or complete loss in different cell types causes synergy in tumor formation. To make this a successful Center: that is, a product that is more than the sum of the parts, coordination is key to insuring function in a highly integrated manner. The Administrative Core of this Center Grant will take responsibility for this to proceed. However, as can be seen from the preliminary data of the projects, many of the experiments presented rely not only on exchanged reagents between the laboratories but more importantly on the development of new intellectual fronts that emerge from convergent experiments. The Parada lab has used mouse models to study the complex cell behaviors of neurofibroma and optic glioma. The Clapp and Ingram labs have used mouse genetics as well as both mouse and human cell populations associated with NF1 to study their signaling and biological properties. Thus, the Center brings together highly complementary approaches and will serve to enrich each of the individual research groups.
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