Targeting Vasculogenesis and Interstitial Hypertension in Neurofibromatosis Type1

描述（由申请人提供）：这是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1型神经纤维瘤病（NF 1）的主要死亡原因。MPNST中的两个关键问题是新血管形成和高间质液压（IFP）。NG 2蛋白聚糖、Nf 1单倍不足（Nf 1 +/-）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。该建议的基本假设是，MPNST中的新血管形成和间质液高血压可以通过抑制NG 2蛋白聚糖和Nf 1单倍不足来抵消。我们建议建立血管生成和血管生成周细胞作为目标，以减少MPNST间质液压力和新生血管。具体目标1。在NF 1小鼠模型中表征NF 1 +/-骨髓源性周细胞和内皮细胞对病理性血管发生的加速贡献。我们将测试从野生型小鼠（Nf 1 +/+）到Nf 1 +/-小鼠的骨髓移植是否减少MPNST中的血管生成并改善存活率。具体目标2。描述NG 2在调节NF 1驱动的新生血管形成和间质性高血压中的作用。我们将确定周细胞-NG 2在MPNST中促进新生血管形成和间质性高血压的程度。我们将测试NG 2和Nf 1单倍不足的联合抑制是否会最大限度地抑制由于NG 2和Nf 1单倍不足之间的协同作用而产生的新血管形成。具体目标3。揭示NG 2在Nf 1单倍不足的新生血管细胞对bFGF的加速反应中的作用。先前的研究确定bFGF超敏反应是Nf 1单倍不足中细胞过度增殖的原因。我们建议确定是否有一个bFGF驱动的协同机制连接NF 1单倍不足和NG 2。具体目标4。确定NF 1小鼠模型中MPNST中高间质液压力的起源。我们将测试NG 2的抑制是否会导致间质液压力的降低，这是由于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。

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.