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：
8134170
负责人：
ALEKSANDER S. POPEL
金额：
$ 5.1万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134170
关键词：
Address Affect Age American American Heart Association Amputation Apolipoprotein E Arteries Arts Atherosclerosis Biological Blood capillaries Blood flow Blood specimen Bromodeoxyuridine Cell Communication Cell Respiration Cessation of life Clinical Clinical Trials Design Collaborations Communities Computer Simulation Corpora Cavernosa Data Diabetes Mellitus Diabetic mouse Disease Excision Extracellular Matrix Extracellular Signal Regulated Kinases Failure Family GAG Gene Gastrocnemius Muscle Gender Gene Activation Gene Delivery Gene Transfer Glycosaminoglycans Goals Growth Growth Factor Receptor Genes Health Heart Diseases Hindlimb Human Hypoxia Inducible Factor Image Injury Ischemia Knowledge Laboratories Lasers Leg Ligands Ligation Link Lower Extremity Measurement Measures Medical Methodology Methods Mitogen-Activated Protein Kinases Modeling Molecular Molecular Models Mus Muscle Muscle Fibers NIH Program Announcements Neuropilin-1 Neuropilins Nitric Oxide Nomenclature Organ PGF gene Pain in lower limb Patients Perfusion Peripheral arterial disease Phosphatidylinositols Phosphotransferases Physiological Placental Growth Factor Plasma Platelet-Derived Growth Factor Pre-Clinical Model Protein Isoforms Protein Kinase Proteins Proto-Oncogene Proteins c-akt Protocols documentation Receptor Protein-Tyrosine Kinases Recombinant Fibroblast Growth Factor Recovery Regimen Relative (related person)Research Personnel Sampling Signal Transduction Signaling Molecule Skeletal Muscle System Systems Biology Testing Therapeutic Time Tissues Universities VEGFC gene Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors Virginia Work Zinc Fingers angiogenesis base capillary clinical application clinically relevant density design diabetic femoral artery human NOS2A protein human NOS3 protein human disease human tissue hypercholesterolemia improved in vivo meetings molecular modeling mouse model multi-scale modeling non-diabetic novel novel therapeutic intervention public health relevance receptor research study response statistics therapeutic angiogenesis tibialis anterior muscle tool

项目摘要

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.

描述（由申请人提供）：外周动脉疾病（PAD）是由动脉粥样硬化引起的，会损害下肢的血液流动，是一个主要的健康问题。目前尚无针对 PAD 的药物疗法能够增加灌注并纠正受损的血流。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，人类的治疗性血管生成试验几乎都失败了，这些失败可能是由于使用了简单的方案和方法，而这些方案和方法的设计没有充分了解调节给定靶点内众多竞争性配体、受体和调节剂的复杂性。组织。为了从根本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利用预测性多尺度计算模型和体内实验的高度协同组合，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来设计改进的新颖的人类疗法。所提出的实验研究是由计算模型的当前预测驱动的。所提出的多尺度模型将连接从分子、到细胞、到微循环、到组织、最后到整个身体的各个水平。类似地，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，从分子到组织和全身测量，它们是调节治疗性血管生成的可行靶标。 PAD 小鼠模型的使用反映了人类疾病与大多数 PAD 患者以及人类样本中发生的糖尿病和高胆固醇血症的密切相关性，这反映出所提出的工作具有重要的转化成分。前三个具体目标将检查小鼠模型。第一个目标将表征具有出色灌注恢复的模型。第二个目标将检查血管生成受损的模型，第三个目标将检查基因转移功效的预测。最后一个目标是检查与小鼠模型中创建的情况相似的人体组织。公共卫生相关性：外周动脉疾病 (PAD) 是由动脉粥样硬化引起的，会损害下肢的血液流动，是一个主要的健康问题。目前尚无针对 PAD 的药物疗法能够增加灌注并纠正受损的血流。该项目将结合计算和实验方法，以便更好地了解身体如何应对腿部动脉阻塞，以及设计新疗法的更好方法。