Our goal is to determine the mechanism by which the highly replicated coronary artery disease (CAD) association at 6q23.2 contributes to disease risk. We have made significant progress toward this goal, demonstrating that: i) functional variation at this locus regulates expression of TCF21 by altering growth factor and developmental pathway transcriptional signaling, as well as post-transcriptional miRNA binding; ii) Tcf21 is expressed in the arterial adventitia and a subset of cells in the media that express low levels of smooth muscle cell (SMC) lineage markers; iii) TCF21 regulates a large number of other CAD associated genes, defining a CAD transcriptional network predicted to regulate growth factor signaling, matrix interaction, and smooth muscle processes; iv) TCF21 promotes cellular proliferation and migration, and inhibits SMC contractile marker gene expression in vitro in human coronary artery SMC; and v) lineage traced Tcf21 expressing cells migrate through the forming plaque and contribute to the SMC lineage at the fibrous cap. Taken together, these data suggest the Central Hypothesis for this proposal: TCF21 regulates fundamental transcription pathways to mediate phenotypic modulation of medial SMC, promoting their dedifferentiation, expansion and migration to the fibrous cap where they again adopt the SMC lineage and contribute to cap integrity and stability. Perturbation of TCF21 expression disrupts this process, increasing the risk of plaque rupture. This hypothesis is also supported by TCF21's known role in development where it mediates expansion of SMC precursor cells of the epicardium and promotes epithelial-mesenchymal transition as these cells migrate into the myocardium and differentiate into coronary SMC. Further studies proposed in this renewal application will utilize genetic mouse models and other reagents and datasets generated in the previous funding period, and will focus on the mechanisms by which TCF21 affects SMC fate and how perturbation of its expression leads to risk for CAD. Specifically, in Specific Aim 1 we propose to use atherosclerosis and plaque rupture models to determine how changes in Tcf21 expression alter the SMC makeup and anatomy of the fibrous cap, thus modifying the risk of plaque rupture.
Specific Aim 2 will investigate the gene regulatory program of Tcf21 in vivo in mouse atherosclerosis as modulated SMC migrate through the plaque and differentiate at the fibrous cap.
Specific Aim 3 will investigate the interaction of TCF21 with known molecular pathways that regulate SMC differentiation state, including the serum response factor-myocardin and the Hippo signaling pathways. Taken together, these studies will significantly advance our understanding of how SMC related processes are regulated by TCF21, and how alteration of these functions contribute to CAD risk.

Public Health Relevance

Significant expense and effort by groups of scientists around the world has led to identification of regions of the human genome that are associated with the genetic risk for various forms of cardiovascular disease. Additional research is required to understand the specific genes involved, and how they work to contribute to the disease process. Such information will allow the development of better therapeutics for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL109512-06
Application #
9101535
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Hasan, Ahmed AK
Project Start
2011-07-20
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Liu, Boxiang; Pjanic, Milos; Wang, Ting et al. (2018) Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci. Am J Hum Genet 103:377-388
Carcamo-Orive, Ivan; Huang, Ngan F; Quertermous, Thomas et al. (2017) Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. Arterioscler Thromb Vasc Biol 37:2038-2042
Assimes, Themistocles L; Lee, I-T; Juang, Jyh-Ming et al. (2016) Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium. PLoS One 11:e0138014
Knowles, Joshua W; Xie, Weijia; Zhang, Zhongyang et al. (2016) Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J Clin Invest 126:403
Winkler, Thomas W (see original citation for additional authors) (2016) Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet 12:e1006166
Priest, James R; Osoegawa, Kazutoyo; Mohammed, Nebil et al. (2016) De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet 12:e1005963
Quertermous, Thomas; Ingelsson, Erik (2016) Coronary Artery Disease and Its Risk Factors: Leveraging Shared Genetics to Discover Novel Biology. Circ Res 118:14-6
Pjanic, Milos; Miller, Clint L; Wirka, Robert et al. (2016) Genetics and Genomics of Coronary Artery Disease. Curr Cardiol Rep 18:102
Kojima, Yoko; Volkmer, Jens-Peter; McKenna, Kelly et al. (2016) CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536:86-90
Priest, James Rush; Gawad, Charles; Kahlig, Kristopher M et al. (2016) Early somatic mosaicism is a rare cause of long-QT syndrome. Proc Natl Acad Sci U S A 113:11555-11560

Showing the most recent 10 out of 21 publications