While much of the Pi's previous research has been peripherally related to biomedicine, it was all done as an engineer's approach to solve biomedical problems, focusing on development of new engineering approaches (i.e. materials, fluidic device, imaging techniques, and mechanical conditioning) to tackle tissue in vitro from a viewpoint of mechanical engineering, based on only a basic understanding of biomedical situation. The proposed training opportunity would provide the PI with an in-depth knowledge of vascular pathology, cell signal transduction, animal and clinical experimentation, as well as added knowledge in imaging, fluid dynamics and mechanobiology in the context of vascular medicine. The career development plan proposed here will greatly help the PI grow in a trans-disciplinary field at the intersection of flow dynamics, cell molecule biology, and vascular medicine. Arterial stiffening is recognized as an important factor of cardiovascular events and increased arterial pulse pressure, a direct consequence of stiffening, has been used to guide pharmaceutical treatment for a variety of systemic vascular diseases. The overall hypothesis of the research project is that increased stiffness of large pulmonary arteries contributes to structural and functional alterations in distal pulmonary arteries, characteristics of pulmonary arterial hypertension, and stiffened arteries play such a pathogenic role in vascular diseases via the modulation of flow pulsatility which causes and/or perpetuates inflammation and thrombosis in the distal PA circulation. To test this hypothesis, three specific aims will be studied: (1) Determine the relationship between pulmonary arterial stiffness and flow pulsatility in hierarchical pulmonary vasculature;(2) Determine effects of flow pulsatility on functional activation of PA endothelial cells;and (3) Determine the molecular mechanisms in flow-induced endothelial activation.

Public Health Relevance

This research program will explore a new mechanism to improve understanding pulmonary vascular diseases. Insights into the mechanism may facilitate development of novel diagnostic and therapeutic strategies that offer an improved quality of life and increased survival rate of affected patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25HL097246-04
Application #
8516087
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$145,800
Indirect Cost
$10,800
Name
University of Colorado at Boulder
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Floren, Michael; Bonani, Walter; Dharmarajan, Anirudh et al. (2016) Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. Acta Biomater 31:156-66
Floren, Michael; Tan, Wei (2015) Three-dimensional, soft neotissue arrays as high throughput platforms for the interrogation of engineered tissue environments. Biomaterials 59:39-52
Elliott, Winston; Scott-Drechsel, Devon; Tan, Wei (2015) In Vitro Model of Physiological and Pathological Blood Flow with Application to Investigations of Vascular Cell Remodeling. J Vis Exp :e53224
Wingate, Kathryn; Floren, Michael; Tan, Yan et al. (2014) Synergism of matrix stiffness and vascular endothelial growth factor on mesenchymal stem cells for vascular endothelial regeneration. Tissue Eng Part A 20:2503-12
Tan, Yan; Tseng, Pi-Ou; Wang, Daren et al. (2014) Stiffening-induced high pulsatility flow activates endothelial inflammation via a TLR2/NF-κB pathway. PLoS One 9:e102195
Scott, Devon; Tan, Yan; Shandas, Robin et al. (2013) High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression. Am J Physiol Lung Cell Mol Physiol 304:L70-81
Li, Min; Tan, Yan; Stenmark, Kurt R et al. (2013) High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB. Cardiovasc Eng Technol 4:26-38
Su, Zhenbi; Tan, Wei; Shandas, Robin et al. (2013) Influence of distal resistance and proximal stiffness on hemodynamics and RV afterload in progression and treatments of pulmonary hypertension: a computational study with validation using animal models. Comput Math Methods Med 2013:618326
Guo, Dong-Jie; Zhang, Hao; Li, Jia-Bo et al. (2013) Fabrication and adhesion of a bio-inspired microarray: capillarity-induced casting using porous silicon mold. J Mater Chem B Mater Biol Med 1:379-386
Madhavan, Krishna; Elliott, Winston H; Bonani, Walter et al. (2013) Mechanical and biocompatible characterizations of a readily available multilayer vascular graft. J Biomed Mater Res B Appl Biomater 101:506-19

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