The molecular mechanisms of SMAD3-mediated coronary disease risk

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Project Summary Despite major advances in therapies, coronary artery disease (CAD) remains the leading killer in the US and worldwide. Identification of risk factors and understanding their underlying biological processes are urgently needed to develop innovative new therapies. Numerous genetic loci have been associated with an increased risk for coronary artery disease (CAD) in genome wide association studies (GWAS). Now efforts are needed to identify causal genes in these loci and link them to specific cellular processes and signaling pathways. Smooth muscle cells (SMC) in the vascular wall express a majority of CAD-associated genes identified in GWAS. Recently, SMAD3 has been identified as the CAD causal association at 15q22.33. Developmental biology as well as our preliminary data suggest SMAD3 may modify cell-fate decisions of phenotypically modulated SMC in the vascular walls in the setting of vascular stress. This led to our central hypothesis that SMAD3 governs a transcriptional network that inhibits protective SMC phenotypic modulation in response to vascular stress. The series of experiments described herein aim to characterize the cellular mechanisms by which perturbation of smooth muscle Smad3 expression modulates atherosclerotic lesions, as well as identify the genetic program regulated by SMAD3 in human coronary artery smooth muscle cells. Aim 1 utilizes a murine atherosclerosis model with SMC-specific deletion of Smad3 and concurrent lineage tracing. We will investigate the effect of Smad3 expression on SMC cell fate and resulting disease anatomy. We will then apply single cell transcriptional profiling of lesion cells to examine the transcriptional program in different SMC progenies, and combine these datasets to understand how CAD risk is mediated by Smad3 specifically in SMC at the cellular level. Aim 2 applies a human coronary artery smooth muscle cell model to study the transcriptional program regulated by SMAD3 through genome-wide identification of enhancers bound by SMAD3 and their transcriptional regulatory effects. We will also overlap the finding with data from another smooth-muscle-expressed CAD-risk-associated transcription factor TCF21, to further our understanding of the SMC transcriptional program that regulates CAD risk. Together, these studies will significantly expand our understanding of the role of transcription factors SMAD3 and TCF21 expressed by SMCs in CAD, and significantly advance our understanding of mechanisms by which causal variation mediates risk for CAD with the hope of leading to novel therapeutic strategies in the future.