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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101200-03
Application #
8253755
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Larkin, Jennie E
Project Start
2010-04-13
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$930,501
Indirect Cost
$158,137
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Noren, David P; Chou, Wesley H; Lee, Sung Hoon et al. (2016) Endothelial cells decode VEGF-mediated Ca2+ signaling patterns to produce distinct functional responses. Sci Signal 9:ra20
Hess, Daniel L; Annex, Brian H (2016) Deficient CDKN2B Expression: A Double Hit for PAD. Circ Res 118:190-2
Clegg, Lindsay Wendel; Mac Gabhann, Feilim (2015) Site-Specific Phosphorylation of VEGFR2 Is Mediated by Receptor Trafficking: Insights from a Computational Model. PLoS Comput Biol 11:e1004158
Clegg, Lindsay E; Mac Gabhann, Feilim (2015) Systems biology of the microvasculature. Integr Biol (Camb) 7:498-512
Heuslein, Joshua L; Li, Xuanyue; Murrell, Kelsey P et al. (2015) Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Rarefaction and Estimation of Skeletal Muscle Perfusion in Peripheral Arterial Disease. Microcirculation 22:360-9
Dokun, Ayotunde O; Chen, Lingdan; Okutsu, Mitsuharu et al. (2015) ADAM12: a genetic modifier of preclinical peripheral arterial disease. Am J Physiol Heart Circ Physiol 309:H790-803
Chu, Liang-Hui; Vijay, Chaitanya G; Annex, Brian H et al. (2015) PADPIN: protein-protein interaction networks of angiogenesis, arteriogenesis, and inflammation in peripheral arterial disease. Physiol Genomics 47:331-43
Chu, Liang-Hui; Annex, Brian H; Popel, Aleksander S (2015) Computational drug repositioning for peripheral arterial disease: prediction of anti-inflammatory and pro-angiogenic therapeutics. Front Pharmacol 6:179
Clegg, Lindsay E; Mac Gabhann, Feilim (2015) Molecular mechanism matters: Benefits of mechanistic computational models for drug development. Pharmacol Res 99:149-54
Zhao, Chen; Popel, Aleksander S (2015) Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer. PLoS Comput Biol 11:e1004612

Showing the most recent 10 out of 37 publications