Coronary artery disease (CAD) and its consequences remain the single largest cause of death in the United States. Epidemiologic studies have established the key roles of several risk factors for coronary artery disease (CAD). However, there is significant overlap in extent and severity of established CAD risk factors between disease and control populations. This suggests that the disease in the general population cannot be accounted for by these risk factors alone and leaves open the question of how to identify novel risk factors. Through a series of studies, we recently identified a loss of function mutation in the Wnt co-receptor LRP6 (LRP6R611C) that underlies a Mendelian form of coronary artery disease, diabetes and metabolic syndrome. The characterization of the mutation has shown that it impairs ligand binding, reduces LRP6 phosphorylation and nuclear beta-catenin localization in response to Wnt stimulation, and subsequently impairs downstream Wnt signaling. Since our initial discovery, impaired Wnt signaling has shown to be a risk factor for CAD in multiple clinical and experimental studies. Discovery of this disease gene and its link to altered canonical Wnt signaling has provided an exceptional opportunity for identification of novel disease pathways. Through homologous recombination, we have generated mice with the LRP6R611C mutation. LRP6R611C mice replicate most human phenotypes, including arterial intimal hyperplasia on high fat diet and develop extremely diffuse and proliferative CAD when they are homozygote for the disease allele. We propose ( 1) to determine the origin of the neointimal cell (2) to examine the role of "canonical" Wnt-catenin signaling in neointima formation and (3) to assess the contribution of bone marrow derived cells (BMD) to neointima formation, by fate mapping, genetic rescue and generation of bone marrow chimeras.

Public Health Relevance

Abstract: Coronary artery disease is the major cause of mortality We have identified a mutation in a gene called LRP6, which causes early coronary artery disease. We propose to study the mechanism of these diseases in a mouse model of this mutation in order to identify novel drug targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122830-01
Application #
8674294
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Olive, Michelle
Project Start
2014-04-01
Project End
2018-01-31
Budget Start
2014-04-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$541,125
Indirect Cost
$216,125
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Song, Kangxing; Wang, Shuxia; Huang, Bihui et al. (2014) Plasma cardiotrophin-1 levels are associated with hypertensive heart disease: a meta-analysis. J Clin Hypertens (Greenwich) 16:686-92