Role of Drebrin in Vascular Smooth Muscle Remodeling

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): Integral to the pathogenesis of atherosclerosis is the transformation of vascular smooth muscle cells (SMCs) from a contractile to a proliferative/migratory phenotype. This transformation also underlies the arterial remodeling associated with hypertension and restenosis following angioplasty and stenting. On a molecular level, this SMC transformation involves cytoskeletal signaling and calcium signaling pathways. Transient receptor potential (TRP) channels are a family of nonselective cation channels which have been implicated in the modulation of calcium influx during vascular remodeling. Critical missing details include what proteins link TRP channels to cytoskeletal signaling pathways and how these proteins influence SMC migration. We have previously shown that TRP channels require the scaffolding protein Homer 1 for proper function. Homer 1 associates with Drebrin, an actin-binding protein highly expressed in SMCs--as we showed using yeast-two hybrid studies, in vitro binding studies, and mutational analyses. In Preliminary Studies, reducing Drebrin expression with siRNA produced spontaneous calcium influx similar to that we observed in the absence of Homer 1. Our Preliminary Studies also show that, compared with WT SMCs, SMCs from Drebrin haploinsufficient (Dbn-/+) mice migrate faster and have increased basal TRP channel activity. We also found that Drebrin expression is upregulated in response to arterial injury, suggesting a role for Drebrin in the regulation of vascular remodeling. Because of the importance of TRP channels in SMC migration and the importance of Drebrin/Homer scaffolds in regulating TRP channels, we plan to test the hypothesis that the Drebrin inhibits SMC transformation to the proliferative/migratory phenotype through regulation of TRP channel function. To test this hypothesis, we will pursue the following Specific Aims. 1) To determine the role of Drebrin in TRP channel regulation in SMCs. We hypothesize that Drebrin loss of function will result in TRP channel dysregulation characterized by increased TRP channel activity and Ca2+ influx. 2) To determine the effect of Drebrin on SMC migration and proliferation. We hypothesize that TRP channel dysregulation observed in Drebrin loss-of-function models will result in increased migration and proliferation compared with controls, both in vitro and in vivo. 3) To determine the effect of Drebrin on hypertensive arterial remodeling. We expect that, compared with WT, Dbn-/+ mice will exhibit similar hypertensive responses but increased medial expansion in response to angiotensin II-induced hypertension. The research proposed in this application is innovative because it focuses on TRP channel regulation by a protein complex, comprising Homer 1 and Drebrin, whose role in the vasculature is currently unknown. The impact of our studies will be to provide critical insights into the function of TRP-regulatory scaffolding proteins which link TRP channel activation with cytoskeletal signaling complexes during SMC migration.