Vascular smooth muscle cell (SMC) differentiation is a very important process during vasculogenesis and angiogenesis, and it is well recognized that alterations in SMC phenotype play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. During the previous funding period we used high throughput sequencing and computational biology to study chromatin structure and transcription factor binding in human aortic SMCs on a genome-wide level. Our work has led to the identification of previously unrecognized SMC-selective proteins, to the characterization of genetic mechanisms that regulate SMC contractility and blood pressure, and to novel transcription mechanisms that regulate SMC-specific gene expression. Using mass spec approaches we recently identified the SMC-selective methyltransferase, PRDM6, as a myocardin factor interacting protein and have cell culture and in vivo data that PRDM6 is required for the maintenance of SMC differentiation and blood pressure. Importantly recent human genetic study described PRDM6 coding mutations that cause patent ductus arteriosis, and GWAS have identified a locus in PRDM that was associated with BP regulation and intracranial aneurysm.
In Aim 1 we will identify the transcription mechanisms and human genetic variations that regulate PRDM6 the SMC-specific expression of PRDM6. Since the mechanisms by which PRDM6 regulates gene expression are completely unknown, in Aim2 we will use genome-wide approaches to identify direct PRDM6 targets, and we will test whether PRDM6 regulates MRTF-A activity by direct methylation.
In Aim 3 we will continue to evaluate the contributions of PRDM6 to the regulation of blood pressure and SMC phenotype in vivo using our conditional SMC-specific PRDM6 knockout mice. We have also established collaborations with clinical cardiovascular research teams at the University of North Carolina to begin to examine the correlation between PRDM6 genotype and hypertension in local populations.
Vascular smooth muscle cell differentiation is a very important process during blood vessel development and it is well recognized that alterations in this process play a role in the progression of several cardiovascular disease states including hypertension, restenosis, and atherosclerosis. Our proposal examines the molecular and cellular mechanisms that control smooth muscle differentiation and should help to identify novel therapeutic targets for the treatment of these diseases.
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