Systems Biology of Angiogenesis in Peripheral Arterial Disease

周围动脉疾病血管生成的系统生物学

基本信息

批准号：
9908148
负责人：
ALEKSANDER S. POPEL
金额：
$ 81.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-13 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908148
关键词：
Address Affect Angiopoietins Anti-Inflammatory Agents Atherosclerosis Autocrine Communication Blood Vessels Blood flow Cell surface Cells Cessation of life Clinical Clinical Trials Communication Complex Complication Computer Models Data Disease Endothelial Cells Endothelium Environment Equilibrium Extravasation Functional disorder Generations Growth Growth Factor Heart Rate Hypoxia Immune Inflammation Ischemia KDR gene Leg Life Ligands Limb structure Mediating Medical Modeling Muscle Fibers Myocardial Infarction Nuclear Paracrine Communication Pathway interactions Patients Perfusion Peripheral arterial disease Permeability Phenotype Play Process Proteins Receptor Cell Receptor Protein-Tyrosine Kinases Recovery Regulation Role Signal Pathway Signal Transduction Stroke System Systems Biology TIE-2 Receptor Testing Therapeutic Time Tissues VEGFA gene Validation Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors Vascular Permeabilities Woman angiogenesis artery occlusion base computer framework design dimer experimental study improved macrophage men predictive modeling receptor response targeted treatment therapeutic angiogenesis therapy outcome trafficking transcription factor

项目摘要

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.

概括外周动脉疾病（PAD）是全身动脉粥样硬化的主要并发症。 PAD 影响 8 岁以上美国有数百万患者，世界各地还有数百万患者。 PAD 患者面临以下问题：由于动脉闭塞，血液流向腿部，因此他们中风和心脏病的发病率很高。对于改善灌注以治疗 PAD 的药物治疗存在大量未满足的需求；目前，尚无医疗治疗可有效增加 PAD 患者腿部的血流量。大量临床试验试图增加血管生成未能为 PAD 提供持久的临床改善。此外，其原因还在于与外周动脉疾病相关的高心脏病发作率、中风和死亡率尚不完全清楚。为了满足改善 PAD 血流的药物治疗的需求，我们需要更好地了解什么控制 PAD 中的血管生成。我们的方法是整合详细的机械多尺度计算具有 PAD 特异性实验数据的模型来模拟 PAD 的病理生理学和治疗。该项目基于以下主张：外周动脉疾病 (PAD) 的治疗方法将通过培养血液来实现容器：稳定、无泄漏或畸形；并且不会促进不良炎症。因此，我们假设 PAD 治疗策略的主要焦点一定是促进正常细胞的生长血管，包括调节免疫细胞以实现最佳的血管生成。为了推进计算作为治疗性血管生成的框架，我们将构建一个包含 VEGFA 的综合信号网络及其内皮受体 VEGFR1、VEGFR2 和 VEGFR3、共同受体和相关途径，血管生成素 (Ang)-Tie，在血管渗漏和血管稳定性中发挥重要作用。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，并设计和测试可以将系统转向促血管生成的策略，促稳定性、不渗漏和抗炎表型。该项目将产生重要信号通路的预测性、经过实验验证的模型，其中与 PAD 的具体相关性。它将推进集成相互依赖信号传导建模的最先进技术细胞和组织水平的途径。该项目将有助于更好地了解 PAD 的基本原理及其决定因素以及转化应用。