Nationally, coronary artery disease is a tremendous health care burden. Current therapies for coronary artery disease suffer from multiple risks to the patient including restenosis, thrombosis, infection, and other graft disease. A completely biological bioartificial artery graft would circumvent these issues and improve the outcome for sufferers of coronary artery disease. Fibrin-based tissue engineering has already shown significant progress but as yet has not produced a bioartificial artery with sufficient mechanical strength for implantation without risk. A new strategy is needed to exploit signaling pathways for cellular stimulation. The hypothesis for the proposed work is that: Prolonged ERK signaling during in vitro culture will improve the mechanical strength of fibrin-based bioartificial arteries, via stimulation of type I collagen transcription and increased collagen content. By manipulating extracellular signal-regulated kinase (ERK) signaling by the cells seeded in tubular fibrin- based constructs, this project will improve the collagen content of bioartificial arteries and ultimately their mechanical strength.
The specific aims of the proposed work are as follows: #1. Establish that ERK activity is necessary for the production of mechanically strong bioartificial arteries. #2. Promote prolonged ERK activation in bioartificial arteries by inhibiting negative feedback pathways. #3. Promote prolonged ERK activation in bioartificial arteries by mechanical stimulation. The primary readouts for the response to ERK signal manipulation will be type I collagen transcription, using a luciferase reporter, collagen content, using a biochemical assay, and mechanical strength, using mechanical testing systems. Significant training in tissue engineering and biomechanics from experts at the University of Minnesota will be a key goal for this fellowship. It is expected that this project will produce bioartificial arteries that can withstand physiological blood pressure.
The proposed research will accelerate the production of a completely biological implantable bioartificial artery, which is a current need for proper treatment of coronary artery disease. By manipulating cellular signaling during artery development, collagen content will be increased, leading to enhanced mechanical strength.
|Weinbaum, Justin S; Schmidt, Jillian B; Tranquillo, Robert T (2013) Combating Adaptation to Cyclic Stretching By Prolonging Activation of Extracellular Signal-Regulated Kinase. Cell Mol Bioeng 6:279-286|