Research Portfolio

Funding Opportunities

Join our Mailing List
Join our mailing list to be notified of new funding opportunities.

Your Email

To receive information about funding opportunities, events, and program updates.



Analysis of tobacco toxin-genetic interactions through study of the dioxin-AHR pathway

Institution: Stanford University
Investigator(s): Thomas Quertermous,
Award Cycle: 2019 (Cycle 30) Grant #: T30IP0999 Award: $589,712
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Pilot Award
Abstracts

Initial Award Abstract
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.