Systems Biology of Angiogenesis in Peripheral Arterial Disease

摘要 外周动脉疾病(PAD)是系统性动脉粥样硬化的主要并发症。PAD困扰着超过8人 美国有数百万名患者，世界各地有数百万名患者。患有PAD的患者从减少 动脉闭塞导致血液流向腿部，他们中风和心脏病发作的几率很高。 有一个巨大的未得到满足的医疗需求，以改善血流灌注治疗PAD；目前，没有 治疗有效地增加了PAD中腿部的血流量。无数临床试验试图增加 血管新生未能为PAD提供长期的临床改善。此外，之所以会出现这样的情况 与PAD相关的心脏病发作、中风和死亡的高发生率只是不完全的了解。 为了满足这种改善PAD血流的药物治疗的需要，我们需要更好地了解 控制PAD中的血管生成。我们的方法是集成详细的机械性多尺度计算 模型用PAD特有的实验数据来模拟PAD的病理生理和治疗。 这个项目是基于这样一个命题，即PAD的治疗方法将通过增加血液来实现 血管：稳定、不渗漏或畸形；不促进不良炎症。因此，我们 假设PAD治疗策略的主要重点必须是促进正常儿童的生长 血管，包括调节免疫细胞以实现最佳的血管生成。以推进计算 治疗性血管生成的框架，我们将建立一个包括VEGFA的综合信号网络 及其内皮受体VEGFR1、VEGFR2和VEGFR3，共受体，以及相关的途径， 血管生成素(Ang)-Tie，在血管渗漏和血管稳定中起重要作用。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 巨噬细胞极化，并设计和测试策略，可以将系统转变为促血管生成， 稳定、无渗漏和抗炎表型。 该项目将导致重要信号通路的预测性、实验验证的模型， 与PAD的具体相关性。它将在建模集成的相互依赖的信号方面达到最先进的水平 在细胞和组织水平上的通路。该项目将使我们从根本上更好地了解PAD 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.