Targeting Vasculogenesis and Interstitial Hypertension in Neurofibromatosis Type1

描述(由申请人提供)：这是一份R21申请的重新提交。恶性周围神经鞘瘤(MPNST)是最常见的恶性肿瘤，也是导致1型神经纤维瘤病(NF1)死亡的主要原因。MPNST的两个关键问题是新生血管和高间质液体压(IFP)。NG2蛋白多糖、NF1单倍体功能不全(NF1+/-)和新生血管细胞对新生血管刺激的加速反应是这两个问题的基础。这一建议的基本假设是，MPNST中的新生血管和间质液体高血压可以通过抑制NG2蛋白多糖和NF1单倍体不足来抵消。我们建议同时建立血管生成和血管生成周细胞作为靶点，以降低MPNST的间质液体压力和新生血管。具体目的1.研究NF1+/-骨髓源性周细胞和内皮细胞在NF1小鼠模型中对病理性血管生成的加速作用。我们将测试从野生型小鼠(Nf1+/+)到Nf1+/-小鼠的骨髓移植是否减少了血管生成并提高了MPNST的存活率。具体目的2.表征NG2在NF1驱动的新生血管形成和间质性高血压中的调节作用。我们将确定周细胞-NG2在MPNST中促进新生血管和间质性高血压的程度。我们将测试NG2和NF1单倍体不足的联合抑制是否会最大限度地抑制由于NG2和NF1单倍体不足之间的协同作用而导致的新生血管形成。具体目的3.揭示NG2在NF1单倍体缺陷新生血管细胞对碱性成纤维细胞生长因子加速反应中的作用。以往的研究证实，碱性成纤维细胞生长因子高敏感性是NF1单倍体功能不全患者细胞过度增殖的原因。我们建议确定是否存在碱性成纤维细胞生长因子驱动的协同机制将NF1单倍体不足与NG2联系起来。具体目的4.明确NF1小鼠模型MPNST高间质液体压的来源。我们将测试NG2的抑制是否会通过减少周细胞的异常数量及其异常收缩特性来降低肿瘤内的压缩收缩力，从而导致间质液体压力的降低。

DESCRIPTION (provided by applicant): 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.