Analysis of tobacco toxin-genetic interactions through study of the dioxin-AHR pathway
Abstracts
Initial Award Abstract |
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Tobacco is the leading cause of preventable death in the United States. Although half of these deaths are
due to cardiovascular (CV) disease, the molecular mechanism of how tobacco leads to increased CV
mortality is not well understood. How we respond to tobacco exposure is known to be genetically determined
- for example, a person with so-called 'good genes" may live a long life despite smoking heavily. Such
interaction between genes and the exposures are known as gene-environment interaction (GxE). Very little is
known of how these GxE are regulated or which genes are responsible. Leveraging the exponential growth in
human genetic findings related to cardiovascular disease and what we know about genes that respond to the
environment, this study will identify a novel mechanism of how tobacco smoke and other environmental toxins
can affect the disease process in the artery of patients and how a person's genetic makeup can vary the way
the artery responds. We are particularly interested in how the smooth muscle cells (SMC) that make up the
majority of the artery wall responds to the tobacco toxins. We hypothesize that a gene called Aryl
Hydrocarbon Receptor (AHR) can affect how SMC participate in the atherosclerotic plaque formation in
response to tobacco exposure, and propose to use mouse models of atherosclerosis, SMC tracking
and high-throughput RNA sequencing at single-cell resolution to answer this question. When this pilot project
is completed, we will: i) have generated a strong model of how dioxin-containing compounds increase
atherosclerosis, including the cell types involved and transcriptional program regulated, and ii) begin to
understand how AHR regulates phenotypic changes in SMC and how AHR affects atherosclerosis. |
