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Funding Agency:

National Institutes of Health / NHLBI

Principal Investigator:

K. Craig Kent, MD

Labs:

Dr. Guo's Lab, Dr. Kent's Lab

Division:

Vascular Surgery

Project Summary:

Every year more than one million Americans require interventions to treat atherosclerotic vascular disease. Unfortunately these interventions trigger the development of recurrent disease or restenosis of the treated vessel. Although preventative therapies have been developed, restenosis still develops in 10-15% of coronary and up to 80% of lower extremity interventions (depending upon the vascular bed). Further insights into the mechanism that underlies restenosis will aid in the development of improved therapeutics. Two major processes contribute to restenosis: 1) thickening of the neointima, or termed intimal hyperplasia, and 2) changes in the vessel wall diameter resulting in either constrictive or adaptive remodeling. Our previous discoveries verify that TGFβ is a dominant factor involved in both of these processes. The role of the cytokine TGFβ in vascular disease has been a conundrum because of the paradox that in vitro, TGFβ produces a highly differentiated smooth muscle cell (SMC) phenotype, however in vivo, TGFβ stimulates SMC de-differentiation and intimal hyperplasia. We have discovered over the past grant period, a unique explanation for this conundrum: elevated levels of Smad3 that develop following vascular intervention, transform TGFβ into a stimulant of SMC de-differentiation, proliferation, migration and inflammation (MCP-1 production), and an inhibitor of apoptosis, all signature behaviors that promote intimal hyperplasia. Surprisingly, elevated levels of TGFβ and Smad3 following arterial intervention also produce the favorable by-product of adaptive remodeling or vessel wall expansion. Inspired by these provocative findings, we are eager to continue our investigations of TGFβ/Smad3 with the goal of 1) gaining further insights into the pathophysiology of restenosis, and 2) developing new strategies to inhibit restenosis via manipulation of Smad3 signaling and/or SMC dedifferentiation.

In Specific Aim-1, we will dissect and differentiate the pathways through which TGFβ/Smad3 stimulates intimal hyperplasia (pro-restenosis) versus enhances adaptive remodeling (antirestenosis), taking advantage of a series of mutants that produce differential transcription of Smad3-responsive genes. In Specific Aim-2, we aim to better understand the factors through which TGFβ/Smad3 produces SMC de-differentiation with the theory that blocking de-differentiation will prevent intimal hyperplasia. In Specific Aim-3, we will design therapies to block Smad3 through the use of Smad3-targeting microRNAs or an inhibitory peptide that competes with the Smad3-binding protein SARA.

Our ultimate goal is to identify agents that inhibit intimal hyperplasia and enhance adaptive remodeling, thus effectively preventing the development of recurrent disease following vascular interventions, a process associated with substantial cost, morbidity and mortality.

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