Smad3-mediated gene-environment interaction and risk of tobacco-induced aneurysms

Stanford University, Stanford CA

Investigators

Abstract

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) is one of the most dreaded and fatal complications of tobacco use. Over 80% of people with a ruptured AAA will die, over 50% of them before reaching the hospital. Medical therapies for AAA are limited, and those with severe disease require surgical repair. There is an urgent need to develop better ways to prevent and slow the development of AAA. Clinical observations suggest two distinct avenues of potential intervention: one focused on understanding the genetic risks that lead to AAA, and the other focused on the epigenetic modifiers associated with AAA development. Our current understanding of the exact mechanism of either factor is impeded due to limitations in previously employed AAA models. This study brings together the expertise of two vascular biologists to tackle this problem: MPI Philip Tsao, who spearheaded many of the human genetic studies of AAA, and Contact PI Paul Cheng, who pioneered single cell transcriptomic and epigenetic techniques in human and murine models of vascular disease. Our proposed study is based on a human genetic risk loci that Dr. Tsao identified by GWAS on Chromosome 15, which regulates SMAD3 level. When combined with Dr. Cheng’s multi-omic vascular biology data, this work points to vascular smooth muscle and adventitial fibroblasts as the key AAA-causing culprit, which is influenced by this loci. This insight enabled the creation of an innovative chronic tobacco-induced AAA model that much more closely resembles human AAA. We will use this improved model to test our central hypothesis that tobacco influences AAA formation through the rewiring of vascular physiological TGFb signaling in two distinct vascular cells to promote a remodeling program, and that this remodeling is particularly prominent in the abdominal aorta due to its unique epigenetic milieu. Our work will leverage the unique combination of our labs’ expertise in genetics, smooth muscle and fibroblast aneurysm biology, and vascular single cell multi-omic analysis to elucidate the genetic, genomic, and epigenetic regulatory mechanisms that govern AAA risk. Aim 1 will employ novel lineage tracing tools in conjunction with the new AAA model and state-of-the-art single cell transcriptomic, epigenetic profiling, and spatial transcriptomics to understand the tobacco-Smad driven cellular behavior that drives AAA formation. Aim 2 will use human aortic cells to determine the precise molecular interaction between tobacco and Smad3 at the protein, DNA, and epigenetic level. Aim 3 will investigate why a certain segment of the aorta is particularly resistant, and how it may be leveraged to better understand pathological cellular programs in AAA. The completion of this study will lead to an unprecedented understanding of different cellular transitions that take place in tobacco-induced AAA. Our study will enrich human genetic data to better link AAA-GWAS loci to causal genes and cells, and identify critical processes at cellular, transcriptional, epigenetic, and protein interaction levels that are ripe to target as novel AAA therapy.