Systems Biology of Angiogenesis in Peripheral Arterial Disease

总结 外周动脉疾病（PAD）是系统性动脉粥样硬化的主要并发症。PAD影响超过8 在美国和世界各地的数百万患者。PAD患者存在以下问题： 由于动脉闭塞导致血液流向腿部，并且他们遭受高比率的中风和心脏病发作。 对于改善灌注以治疗PAD的医学治疗存在大量未满足的需求;目前，没有医学治疗。 治疗有效地增加了PAD中腿部的血流量。大量的临床试验试图增加 血管生成未能提供PAD的长期临床改善。此外， 与PAD相关的高心脏病发作率、中风率和死亡率还不完全清楚。 为了满足改善PAD血流的药物治疗需求，我们需要更好地了解 控制PAD中的血管生成。我们的方法是将详细的机械多尺度计算 使用PAD特异性实验数据建立模型，以模拟PAD的病理生理学和治疗。 该项目基于这样的主张，即PAD的治疗方法将通过生长血液来实现 血管：稳定，无渗漏或畸形;不促进不良炎症。所以我们 假设PAD治疗策略的主要重点必须是促进正常的生长， 血管，包括调节免疫细胞以实现最佳血管生成。为了推进计算 治疗性血管生成的框架，我们将建立一个整合的信号网络，包括VEGFA 及其内皮受体VEGFR 1、VEGFR 2和VEGFR 3，共受体，以及相关途径， 血管生成素（Angiopoietin，Ang）-Tie在血管渗漏和血管稳定性中起重要作用.炎症是一种 PAD和其他缺血性疾病的标志，我们将制定基于实验的计算模型 的巨噬细胞极化，并设计和测试策略，可以转向系统的促血管生成， 促稳定性、非渗漏和抗炎表型。 该项目将导致预测，实验验证模型的重要信号通路， 与PAD的具体相关性。它将推进建模的最新技术水平的综合相互依赖的信号 在细胞和组织水平的途径。该项目将导致对PAD有更好的基本了解 及其决定因素和翻译应用。

SUMMARY Peripheral arterial disease (PAD) is a major complication of systemic atherosclerosis. PAD afflicts over 8 million patients in the US and millions more around the world. Patients with PAD have problems from reduced blood flow to the leg resulting from the arterial occlusions and they suffer high rates of stroke and heart attack. There is a large unmet need for medical treatments to improve perfusion to treat PAD; currently, no medical treatment effectively increases blood flow to the leg in PAD. Numerous clinical trials attempting to increase angiogenesis have failed to provide long-lasting clinical improvements in PAD. In addition, the reason for the high rates of heart attack, stroke, and death associated with PAD are only incompletely understood. To meet this need for medical therapies to improve blood flow in PAD, we need a better understanding of what controls angiogenesis in PAD. Our approach is to integrate detailed mechanistic multiscale computational models with PAD-specific experimental data to simulate the pathophysiology and treatment of PAD. This project is based on the proposition that therapeutic approaches in PAD will be realized by growing blood vessels that are: stable, not leaky or malformed; and do not promote adverse inflammation. Therefore, we hypothesize that a major focus of therapeutic strategies in PAD must be on promoting the growth of normal blood vessels, including modulating immune cells for optimal angiogenesis. To advance the computational framework for therapeutic angiogenesis, we will build an integrative signaling network that includes VEGFA and its endothelial receptors VEGFR1, VEGFR2, and VEGFR3, co-receptors, and an associated pathway, Angiopoietin (Ang)-Tie, that plays an important role in vascular leakage and vascular stability. Inflammation is a hallmark of PAD and other ischemic diseases, and we will formulate experiment-based computational models of macrophage polarization, and design and test strategies that can shift the system toward a pro-angiogenic, pro-stability, non-leaky, and anti-inflammatory phenotype. This project will result in predictive, experimentally-validated models of important signaling pathways, with specific relevance to PAD. It will advance state of the art in modeling integrative interdependent signaling pathways at the cellular and tissue levels. The project will lead to a better fundamental understanding of PAD and its determinants and to translational applications.