This is a resubmission of an R21 application. Malignant peripheral nerve sheath tumors (MPNST) are the most common malignant tumor, and the leading cause of mortality in neurofibromatosis type 1 (NF1). Two critical issues in MPNST are neovascularization and high interstitial fluid pressure (IFP). The NG2 proteoglycan, Nf1 haploinsufficiency (Nf1+/-), and accelerated response of neovascular cells to neovascular stimuli are fundamental to both issues. The underlying hypothesis for this proposal is that neovascularization and interstitial fluid hypertension in MPNST can be counteracted by inhibiting both NG2 proteoglycan and Nf1 haploinsufficiency. We propose to establish both vasculogenic and angiogenic pericytes as targets to reduce interstitial fluid pressure and neovascularization in MPNST.
Specific Aim 1. Characterize the accelerated contribution of Nf1+/- bone marrow-derived pericytes and endothelial cells to pathological vasculogenesis in NF1 mouse model. We will test whether bone marrow transplantation from wild type mice (Nf1+/+) to Nf1+/- mice reduces vasculogenesis and improves survival in MPNST.
Specific Aim 2. Characterize the roles for NG2 in modulation of NF1-driven neovascularization, and in interstitial hypertension. We will determine the extent to which pericyte-NG2 contributes to neovascularization and interstitial hypertension in MPNST. We will test whether the combined inhibition of NG2 and Nf1 haploinsufficiency will maximally inhibit neovascularization due to synergy between NG2, and Nf1 haploinsufficiency.
Specific Aim 3. Reveal the role for NG2 in accelerated response of Nf1 haploinsufficient neovascular cells to bFGF. Previous investigations identified bFGF hypersensitivity as a cause of excessive cell proliferation in Nf1 haploinsufficiency. We propose to determine whether there is a bFGF-driven synergistic mechanism linking Nf1 haploinsufficiency and NG2.
Specific Aim 4. Identify the origin of high interstitial fluid pressure in MPNST in the NF1 mouse model. We will test whether inhibition of NG2 results in a decrease in interstitial fluid pressure due to decreasing compressive contractile forces within the tumor by decreasing the abnormal number of pericytes and their abnormal contraction properties. ? ? ?
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