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 mechanisms that underlie restenosis will aid in the development of improved therapeutics. Two major processes contribute to restenosis: 1) thickening of the neointima, termed intimal hyperplasia, and 2) changes in the vessel wall diameter resulting in either constrictive or adaptive remodeling. Our previous discoveries verify that TGF is a dominant factor involved in both of these processes. The role of the cytokine TGF in vascular disease has been a conundrum because of the paradox that in vitro, TGF produces a highly differentiated smooth muscle cell (SMC) phenotype, however in vivo, TGF 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 TG 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 TGF 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 TGF/Smad3 with the goal of 1) gaining further insights into TGF's role in the pathophysiology of restenosis, 2) developing new strategies to inhibit restenosis by manipulating SMC de-differentiation and 3) developing therapeutic strategies to inhibit restenosis by blocking both Smad-dependent and Smad-independent TGF signaling.
In Specific Aim -1, we will dissect and differentiate the pathways through which TGF/Smad3 stimulates intimal hyperplasia (pro-restenosis) versus adaptive remodeling (anti-restenosis), taking advantage of a series of mutants that produce differential expression of Smad3-responsive genes.
In Specific Aim -2, we aim to better understand the factors through which TGF/Smad3 produces SMC de- differentiation with the theory that blocking de-differentiation and/or enhancing differentiation will prevent intimal hyperplasia.
In Specific Aim -3, we will determine the role of Smad-independent pathways in TGF- induced restenosis, and then design combination therapies to simultaneously block Smad3 signaling with a Smad3-inhibiting peptide, and non-Smad pathway(s) with their specific inhibitors. Our ultimate goal is to identify agents that effectively prevent the development of recurrent vascular disease, a process affecting hundreds of thousands of patients each year.
Each year over one million Americans require vascular reconstruction to reopen their narrowed arteries; but recurrent arterial narrowing occurs in 15-80% of these patients. We have discovered that TGF-beta and its signaling protein Smad3 play an important role in the development of this recurrent disease. We propose to better understand why TGF-beta produces recurrent plaque with the goal of developing treatments for this morbid and sometimes deadly pathology.
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