| Start Date: | 3/20/2018 | Start Time: | 1:00 PM |
| End Date: | 3/20/2018 | End Time: | 3:00 PM |
|
Event Description
BIOMED PhD Research Proposal
Title:
The Protective Role of Shear Stress on Endothelial Cell Glucose Metabolism
Speaker:
Sarah Basehore, PhD Candidate, School of Biomedical Engineering, Science and Health Systems, Drexel University
Advisors:
Alisa Morss Clyne, PhD, Associate Professor, Department of Mechanical Engineering and Mechanics, Drexel University
Kenneth A. Barbee, PhD, Professor, Senior Associate Dean, and Associate Dean for Research, School of Biomedical Engineering, Science and Health Systems, Drexel University
Abstract:
Cardiovascular disease is the leading global cause of death, resulting in more than 17.9 million deaths in 2015. Cardiovascular disease risk factors include hypertension, high triglycerides, obesity, reduced high-density lipoprotein cholesterol, and elevated fasting blood sugar. Each metabolic risk factor is associated with endothelial cell (EC) dysfunction, a precipitating factor in cardiovascular disease. EC in unidirectional steady laminar flow (>12 dynes/cm2 shear stress) adapt by aligning and elongating actin fibers parallel to flow. Steady laminar flow promotes a healthy, quiescent EC phenotype in which EC phosphorylate endothelial nitric oxide synthase (eNOS) to produce NO, a vasodilator that is also important in preventing vascular disease. However, when EC fail to adapt to flow, for example in areas of oscillating disturbed flow, they have impaired NO production. Areas of disturbed flow are typically linked to EC dysfunction and diseases such as atherosclerosis. Little is known about how blood flow regulates EC metabolism, despite the importance of EC metabolism in cardiovascular disease.
This research will elucidate how hemodynamics regulate EC glucose metabolism, and how EC glucose metabolism can be modulated to restore EC function in areas of disturbed flow. We hypothesize that steady, laminar flow (shear stress of 20 dynes/cm2) reduces glycolytic flux and eNOS O-GlcNAcylation to promote a healthy endothelial phenotype. We will approach this study by determining how steady laminar and oscillating disturbed flow regulates (1) endothelial glycolytic flux and (2) eNOS O-GlcNAcylation. We will then investigate how activation of shear sensitive pathways can restore EC function (NO production/vasodilation) by (3) overexpressing Kruppel-like factor 2 (KLF2) in pulmonary arterial hypertension endothelial cells to decrease glycolytic activity and eNOS O-GlcNAcylation. We will investigate these aims by adapting human endothelial cells to flow in a cone-and-plate device in vitro; isolating mouse endothelial cells from laminar and disturbed flow arterial regions; cannulating mouse arteries on a microscopy based flow system ex vivo; and inducing pulmonary hypertension in neonatal and adult mouse models in vivo.
This research will help us understand how shear stress regulates EC metabolism and protein O-GlcNAcylation in particular, advancing our understanding of EC dysfunction. In the future, new therapies could be developed to modify metabolism or O-GlcNAcylation levels as a mechanism to treat EC dysfunction and atherosclerosis. |
|
Location:
Bossone Research Center, Room 709, located at 32nd and Market Streets. |
Audience:
Undergraduate StudentsGraduate StudentsFacultyStaff |
|
