BIOMED Ph.D. Research Proposal
Collagen Glycation Induced Modification of Endothelial Cells and Basement Membrane Interactions|
Date: October 16, 2009
at 3:00 PM
Location: Bossone Research Enterprise Center, Room: 709
Dannielle Solomon Figueroa
Research Advisor: Alisa Clyne, Ph.D.
Department Advisor: Todd Doehring
According to the World Health Organization, more than 180 million people worldwide suffer from diabetes. Diabetic patients have a higher associated risk of vascular morbidity and mortality. Both microvascular diseases, such as, retinopathy and nephropathy, as well as macrovascular diseases, such as atherosclerosis and restenosis are increased. Diabetic hyperglycemia, or elevated blood glucose, is a major contributor to these pathologies. Endothelial cells that line the vasculature are dysfunctional in hyperglycemia. Endothelial cell dysfunction is an initiating step in vascular diseases such as atherosclerosis. Hyperglycemia also glycates collagen in the basement membrane underneath the endothelial cells. Glycated collagen then crosslinks in the vascular wall, making a stiffer blood vessel.
In healthy conditions, endothelial cells and the basement membrane form a co-regulatory unit for both biochemical and mechanical stimuli. Endothelial cells sense mechanical stimuli, such as the cyclic stretch of arteries caused by blood flow, and respond by reorganizing their basement membrane adhesions to reorient perpendicular to the stretch direction. Cells further remodel the basement membrane itself by degrading the existing proteins and rebuilding the membrane with new proteins that are oriented in the stretch direction. While endothelial cell interaction with basement membrane has been extensively studied, it is not clear how a disease such as diabetes may disrupt this interaction. Specifically, it is not known how glycated collagen alters the endothelial cell response to stretch. We hypothesize that endothelial cell response to stretch is inhibited by basement membrane collagen glycation due to altered focal adhesion formation and basement membrane remodeling.
To test this hypothesis we designed, fabricated, and tested a custom cell stretching system to apply cyclic, uniaxial stretch to endothelial cells seeded on flexible polydimethylsiloxane (PDMS) membranes. This system provides a mechanism for stimulating endothelial cell mechanical responses and basement membrane remodeling. We will use this system to study collagen glycation-induced modification of the endothelial cell – basement membrane interaction in response to stretch.
Through this research, we will improve our understanding of the biochemical and mechanical interactions of the endothelial cell – basement membrane bidirectional system, and identify targets for improved therapies for people with diabetes.
The Bossone Research Enterprise Center is located at the corner of 32nd and Market Streets.