Systems Biology of Angiogenesis in Peripheral Arterial Disease

描述（由申请人提供）：外周动脉疾病（PAD），由动脉粥样硬化引起，损害血液流向下肢，是一个主要的健康问题。目前还没有能够增加灌注和纠正受损血流的PAD医学治疗方法。治疗性血管生成是治疗组织灌注不足患者的一种策略。然而，在人体中进行的血管生成治疗试验几乎都失败了，这些失败可能是由于使用了简单的方案和方法，这些方案和方法的设计没有充分认识到在给定目标组织中调节众多竞争配体、受体和调节剂的复杂性。为了在基础水平上理解这些现象并开发新的治疗方法，定量计算系统生物学方法与实验测量的协同结合不仅是可取的，而且是绝对必要的。该项目的总体目标是通过预测性多尺度计算模型和体内实验的高度协同结合，获得对PAD血管生成的定量知识和理解；进一步，利用这些知识，设计改进的和新的人类治疗方法。提出的实验研究是由当前计算模型的预测驱动的。提出的多尺度模型将连接从分子到细胞，到微循环，到组织，最后到整个身体的水平。同样，实验测量将在多个尺度上进行，使用血管内皮生长因子（VEGF）和VEGF受体，从分子到组织和系统测量调节治疗性血管生成的可行目标。PAD小鼠模型的使用反映了人类疾病与糖尿病和高胆固醇血症的强烈关联，这发生在大多数人类PAD患者以及人类样本中，反映了所提出的工作具有重要的翻译成分。前三个具体目标将检查小鼠模型。第一个目标是描述一个具有良好灌注恢复的模型。第二个目标将检查受损血管生成的模型，第三个目标将检查基因转移效果的预测。最后一个目标是研究与小鼠模型中创建的情况相似的人体组织。

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD), caused by atherosclerosis that impairs blood flow to the lower extremities, is a major health problem. Currently there are no medical therapies for PAD that have the ability to increase perfusion and correct the impaired blood flow. Therapeutic angiogenesis is a strategy to treat patients that have inadequate tissue perfusion. However, therapeutic angiogenesis trials in humans have almost uniformly failed and these failures may be attributable to the use of simple regimens and approaches that were designed without an adequate appreciation of the complexities that regulate the numerous competing ligands, receptors, and modulators within a given target tissue. To understand these phenomena at the fundamental level and to develop novel therapeutic approaches, quantitative computational systems biology approaches synergistically combined with experimental measurements are not only desirable, but absolutely necessary. The broad goal of the project is to gain a quantitative knowledge and understanding of angiogenesis in PAD, using a highly synergistic combination of predictive multiscale computational modeling and in vivo experiments; and further, using this knowledge, to design improved and novel human therapeutics. The proposed experimental studies are driven by the current predictions of the computational models. The proposed multiscale models will connect the levels from the molecular, to cellular, to microcirculatory, to tissue, and finally to whole body. The experimental measurements will similarly be conducted at multiple scales, using vascular endothelial growth factor (VEGF) and the VEGF receptors, viable targets for the modulation of therapeutic angiogenesis, from the molecular to the tissue and systemic measurements. The use of mouse models of PAD that reflect the strong association of human disease with diabetes and hypercholesterolemia which occur in the majority of patients with PAD in human, as well as human samples, reflect that the proposed work has an important translational component. The first three specific aims will examine mouse models. The first aim will characterize a model with excellent perfusion recovery. The second aim will examine models of impaired angiogenesis and the third will examine predictions of efficacy of gene transfer. The last aim will examine human tissues that parallel the situations created within the mouse models. PUBLIC HEALTH RELEVANCE: Peripheral arterial disease (PAD) is caused by atherosclerosis that impairs blood flow to the lower extremities, is a major health problem. Currently there are no medical therapies for PAD that have the ability to increase perfusion and correct the impaired blood flow. The project will combine computational and experimental approaches to allow a better understanding of how the body responds to blockages in the leg arteries as well as better ways to design new therapies.