PERICYTES IN ANGIOGENESIS IN NEUROFIBROMATOSIS TYPE 1

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DESCRIPTION (provided by applicant): Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders in children. The most common and serious consequence of NF1 is the reduction of life expectancy by neoplasms. The underlying hypothesis for this proposal is that, in addition to angiogenesis mediated by tumor-derived factors, the molecular defect associated with neurofibromatosis type 1 may also promote tumor neovascularization by directly activating the proliferation of vascular pericytes. This proposal will establish pericytes and NG2 proteoglycan, which has a functional role in angiogenesis, as novel cellular and molecular targets for the anti-angiogenic treatment of NF1-associated tumors. Specific Aims: 1) To use pericyte-specific markers to delineate in detail the temporal and spatial relationship between pericytes and endothelial cells in the neovasculature of NF1-derived tumors. 2) To determine whether interference with the function of a key pericyte component, the NG2 proteoglycan, inhibits NF1 tumor vascularization and progression. This will be done through both genetic (i.e. the NG2 null mouse) and immunochemical (i.e. NG2 blocking antibody) approaches. 3) To demonstrate increased proliferation of mural cells in the micro and macrovasculature of embryonic NF1-/- mice, to document the developmental consequences of this phenomenon, and to demonstrate the possibility of rescuing these NF1-associated defects via ablation of NG2. Research Design: 1) de novo and orthotopic xenograft NF1 tumor models will be used to study the details of the vascular pericyte/endothelial cell relationship. 2) The anti-angiogenic efficacy of NG2 neutralizing antibody will be evaluated in a mouse corneal model of NF1 tumor neovascularization. In addition, a breeding strategy will be developed with NF1+/- mice and NG2 knockout mice to yield NF1+/-NG2+/+ and NF1+/- NG2-1- mice. Vascularization of orthotopic NF1-derived glioma xenografts will be compared in these two genotypes. In the absence of xenografts, the investigators will also follow these 2 groups of mice for 2 years in order to compare de novo tumor onset and progression. 3) The investigators will examine the effect of the NF1-/- and NF1-/+ genotypes on microvascularization in embryonic development. The ability of NG2 ablation to rescue micro and macrovascular defects will be determined.