Neurofibromatosis results from mutations in the NFl tumor suppressor gene, which encodes the protein neurofibromin. Vasculopathies constitute an under-recognized source of morbidity and mortality in NF1 patients. NFl patients develop vascular lesions including arterial occlusions and aneurysms. Despite these observations, the function of neurofibromin in coordinating the complex interactions between endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and bone marrow derived cells (BMDCs) for maintainance of blood vessel wall homeostasis in vivo is incompletely understood. Studies outlined in this application will directly address this lack of knowledge and are imperative for understanding the pathogenesis of NF1 vascular disease, rational design of experimental therapeutics, and development of novel biomarkers to predict early vascular disease in NF1 patients prior to sudden cardiovascular decompensation. We developed novel genetically engineered mouse models of both arterial occlusion and aneurysm formation, which recapitulates the human NFl phenotype. Utilizing lineage restricted transgenic mice to ablate Nfl in ECs, VSMCs and BMDCs, we provide preliminary data to support that hypothesis that Nf1 +/- macrophages and upregulation of extracellular matrix protein osteoponfin are the primary effectors of NFl arterial occlusion. Having established the first animal model of NFl aneurysms, we also provide preliminary to support the hypothesis that either neurofibromin deficient VSMCs, ECs or BMDCs and upregulation of osteoponfin orchestrate NFl aneurysm formation. Therefore the specific aims are: (1) Using lineage-restricted transgenic mice, we will specifically ablate Nfl in myeloid cells to test the hypothesis that heterozygous inactivation of Nfl in monocyte/macrophages directly leads to increased neointima formation in Nf1 +/- mice (2) Using both lineage-restricted transgenic mice and bone marrow transplantation to specifically delete one allele of Nf1 in either the VSMCs, ECs or BMDCs, we will determine which specific cell lineage is critical for increased aneurysm formation in vivo. (3) To test the hypothesis that upregulation of osteoponfin accelerates neointima and aneurysm formation in Nf1 +/- mice in vivo, we will intercross OPN -/- and Nf1 +/- mice to generate compound mutants.
Vasculopathies constitute an under-recognized source of morbidity and mortality in NF1 patients, but the molecular mechanism for this manifestation is not understood. Studies outlined in this application will directly address this lack of knowledge and are imperative for understanding the pathogenesis of NFl vascular disease, rational design of experimental therapeutics, and development of novel biomarkers to predict early vascular disease in NF1 patients prior to sudden cardiovascular decompensation.
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