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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：
10368099
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368099
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 multi-scale modeling predictive modeling receptor response targeted treatment therapeutic angiogenesis therapy outcome trafficking transcription factor translational applications

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.

总结

项目成果

期刊论文数量（99）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability.

DOI：
10.1128/spectrum.01671-21
发表时间：
2022-02-23
期刊：
Microbiology spectrum
影响因子：
3.7
作者：
Kovacs-Kasa A;Zaied AA;Leanhart S;Koseoglu M;Sridhar S;Lucas R;Fulton DJ;Vazquez JA;Annex BH
通讯作者：
Annex BH

MicroRNA-146a Regulates Perfusion Recovery in Response to Arterial Occlusion via Arteriogenesis.

MicroRNA-146A通过动脉生成来调节灌注恢复，以应对动脉闭塞。

DOI：
10.3389/fbioe.2018.00001
发表时间：
2018
期刊：
Frontiers in bioengineering and biotechnology
影响因子：
5.7
作者：
Heuslein JL;McDonnell SP;Song J;Annex BH;Price RJ
通讯作者：
Price RJ

Alteration in angiogenic and anti-angiogenic forms of vascular endothelial growth factor-A in skeletal muscle of patients with intermittent claudication following exercise training.

DOI：
10.1177/1358863x11436334
发表时间：
2012-04
期刊：
Vascular medicine (London, England)
影响因子：
0
作者：
Jones WS;Duscha BD;Robbins JL;Duggan NN;Regensteiner JG;Kraus WE;Hiatt WR;Dokun AO;Annex BH
通讯作者：
Annex BH

Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia.