New Roles for VEGFR1 in Angiogenesis

总结 血管内皮生长因子（VEGF）配体家族及其受体酪氨酸激酶家族， 包括VEGF-VEGFR超家族，其在控制血管生长中起核心作用 （血管生成）在发育中、在成人生理学中以及在超过70种疾病中。VEGF和VEGF受体是 因此是许多高死亡率和高发病率疾病的关键治疗靶点。然而结果 通过靶向VEGF和VEGF受体治疗疾病的尝试是混合的。一些成功是 在癌症和视网膜病变的血管生成抑制中可见;但在外周和冠状动脉疾病中， 尽管如此，十几项递送VEGF的人体临床试验未能增加血管生成和灌注， 临床前动物模型的成功。无法成功地将治疗从动物过渡到人类 表明我们对多配体、多受体VEGF-VEGFR系统的了解还不够。只 通过对复杂系统的定量理解，使用一个框架， 小鼠和人类之间的一种有意义的方式，我们将能够成功地做出关于治疗的预测。 迄今为止，大多数受体工作仅集中在内皮细胞表达的三种VEGF中的一种， VEGFR 2，而在大多数内皮细胞中强烈表达的VEGFR 1相对被忽略。 然而，我们最近的研究表明，VEGFR 1的质膜驻留形式具有两个 在内皮细胞生物学中的重要作用：它通过磷酸化STAT 3本身转导信号，不依赖于 VEGFR 2活化;并且其螯合配体，使其与VEGFR 2保持接触并调节VEGFR 2信号传导。 我们称之为VEGFR 1的“信号”作用和“诱饵”作用。配体隔离诱饵 膜结合（m）VEGFR 1的信号传导作用可能有助于血管生成。我们假设 信号传导与诱饵的相对重要性取决于配体和受体的表达，以及 受体运输和稳定性。在这项研究中，我们将使用一种综合方法，将联合收割机的专业知识 我们的实验室：计算建模;小鼠和人类内皮细胞培养测定;和靶向治疗 干预小鼠和人类。这种综合方法将使我们能够分离和量化信号 和诱饵效应，并定义和完善其相对的血管生成的贡献。项目目标是 目的：（1）建立并验证mVEGFR 1的第一个计算模型;（2）定义并量化信号传导， mVEGFR 1的诱饵作用;和（3）预测和测试mVEGFR 1的作用对体内治疗的影响。我们 中心假设是整合mVEGFR 1配体结合， 激活、运输、稳定性和信号传导将确定实现治疗所需的调节， 血管生成这项研究的结果将是更好地了解mVEGFR 1生物学及其对 发展和疾病;我们结合计算和实验的方法将阐明的作用， mVEGFR 1比单独的计算或实验方法更完整。!

SUMMARY The Vascular Endothelial Growth Factor (VEGF) family of ligands, and their receptor tyrosine kinase family, comprise the VEGF-VEGFR superfamily that plays a central role in the control of blood vessel growth (angiogenesis) in development, in adult physiology, and in over 70 diseases. VEGFs and VEGFRs are therefore key therapeutic targets across many high-mortality and high-morbidity illnesses. However, the results of attempts to treat diseases by targeting VEGFs and VEGFRs have been mixed. Some successes have been seen in angiogenesis inhibition for cancer and retinopathy; but in peripheral and coronary artery diseases, over a dozen human clinical trials delivering VEGF have failed to increase angiogenesis and perfusion, despite success in preclinical animal models. This inability to successfully bridge treatment from animals to humans shows that we do not sufficiently understand the multi-ligand, multi-receptor VEGF-VEGFR system. Only through a quantitative understanding of the complex system, using a framework under which we can compare mouse and human in a meaningful way, will we be able to successfully make predictions regarding treatment. Most receptor work to date has focused on just one of the three VEGFRs expressed by endothelial cells, VEGFR2, while VEGFR1, which is robustly expressed in most endothelial cells, has been relatively ignored. However, our recent studies have shown that the plasma membrane-resident form of VEGFR1 has two important roles in endothelial cell biology: it transduces signals itself via phosphoSTAT3, independent of VEGFR2 activation; and it sequesters ligand, withholding it from VEGFR2 and modulating VEGFR2 signaling. We term these the `signaling' role and the `decoy' role of VEGFR1. Both the ligand-sequestering decoy role and signaling role of membrane-bound (m)VEGFR1 likely contribute to angiogenesis. We hypothesize that the relative importance of signaling vs decoy depends on ligand and receptor expression, and on the regulation of receptor trafficking and stability. In this study, we will use an integrative approach to combine the expertise of our labs: computational modeling; mouse and human endothelial cell culture assays; and targeted therapeutic interventions in mice and humans. This integrated approach will enable us to isolate and quantify the signaling and decoy effects, and to define and refine their relative contributions to angiogenesis. The project goals are to: (1) build and validate the first computational model of mVEGFR1; (2) define and quantify the signaling and decoy roles of mVEGFR1; and (3) predict and test the effect of mVEGFR1's roles on therapies in vivo. Our central hypothesis is that a predictive computational framework that integrates mVEGFR1 ligand-binding, activation, trafficking, stability, and signaling will identify the modulations needed to achieve therapeutic angiogenesis. The outcome of this study will be a better understanding of mVEGFR1 biology and its impact on development and disease; our combined computational and experimental approach will elucidate the roles of mVEGFR1 more completely than computational or experimental approaches alone. !