Year 5 (partial)
Blockage of coronary arteries that supply blood to the heart muscle is the major cause of morbidity and mortality in our society. Angioplasty and stenting are used to open the obstructed coronary artery and maintain the arterial patency. In US, ~1.3 million angioplasty and stenting procedures are performed every year to treat coronary artery disease. Although effective in restoring the blood flow, these procedures activate a population of vascular cells resident in the arterial wall to grow into the vesslel lumen, causing re-narrowing (restenosis) of the treated artery months or years later. This arterial re-narrowing is a major hurdle limiting the success of angioplasty and stenting. Mental stents coated with drug inhibitors of cell growth (drug eluting stents, or DES) reduce re-narrowing; however, the safety of DES has raised considerable concerns due to an increased risk of sudden stent occlusion by platelet aggregates (or thrombosis) as well as the need for prolonged anti-platelet therapy, which poses bleeding risks, especially in the elderly population. It is therefore important to define the underlying mechanisms of re-narrowing of injured arteries in order to design new therapies for coronary artery disease.
A population of stem cells resides in the arterial wall. These stem cells are activated when arteries are injured by angioplasty and stenting. Once activated, these cells grow and differentiate into cells that invade the vascular luman and contribute to arterial re-narrowing. We developed new genetic tools to further understand the mechanism of vascular injury and repair. We are using the new genetic tool to define molecular and cellular pathways that control the reaction of stem cells to arterial injury. The goal is to understand how these stem cells are activated by vessel injury, how injury signals these cells to divide and invade the vessel lumen, what molecular effectors control the cellular responses, and how to intercept these signals and effectors to prevent vessel re-narrowing.