Atherosclerotic coronary artery disease (CAD) remains a major cause of death and disability. New biological discoveries are required to transform our understanding of the disease and to spur clinical and therapeutic advances. Of CAD loci identified through recent genome wide association studies (GWAS), many have no apparent association with established risk factors or known mechanisms of atherosclerosis. Few new loci, however, have the combination of a clear candidate gene at the locus, plausible biology, and preliminary evidence that suggest specific translational hypotheses. Through GWAS, we discovered and replicated ADAMTS7 as a novel locus for coronary atherosclerosis. This finding has been reproduced in two other large-scale GWAS initiatives. ADAMTS7 has no relationship to traditional risk factors. This metalloproteinase, however, is expressed in human vascular smooth muscle cell (VSMC) and atherosclerotic lesions and our preliminary studies suggest that Adamts7-/- gene deletion in mice reduces the in vivo neointimal response to femoral artery injury. We hypothesize that ADAMTS7 promotes transition to VSMC synthetic phenotype and accelerates atherosclerosis by cleaving cartilage oligomeric matrix protein (COMP) an endogenous brake on VSMC migration, proliferation and matrix secretion. Here, we propose a series of experiments to:
(Aim 1) define ADAMTS7 structure-function for COMP and develop a high-throughput ADAMTS7 activity assay for use in mouse and human, (Aim 2) examine effects of germline loss-of-function (LOF) and gain-of-function (GOF) of Adamts7 on VSMC phenotype, vascular injury and atherosclerosis in mouse models, and (Aim 3) interrogate functional impact and CAD association of rare and low frequency non-synonymous ADAMTS7 alleles in human. Our investigative team is well positioned to execute these translational studies and advance our understanding of causation, directionality and mechanisms of ADAMTS7 action in atherosclerosis.
Through GWAS, we have identified and validated ADAMTS7 as a novel gene for coronary atherosclerosis and heart disease. Little is known of ADAMTS7 function in the vasculature. In this proposal, we will define structure-function of ADAMTS7 interactions with target proteins, assess the effects of loss of function and gain of function on mouse atherosclerosis and VSMC function, and interrogate non-synonymous variants discovered upon sequencing of ADAMTS7 in humans for potential loss of function mutations that reduce risk of CAD. Our team is well positioned to advance understanding of ADAMTS7 mechanisms in atherosclerosis, thus establishing if this enzyme might be a valid therapeutic target for heart disease.
|Ballantyne, Rachel L; Zhang, Xuan; NuÃ±ez, Sara et al. (2016) Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits. Hum Mol Genet 25:3125-3141|
|Ferguson, Jane F; Xue, Chenyi; Hu, Yu et al. (2016) Adipose tissue RNASeq reveals novel gene-nutrient interactions following n-3 PUFA supplementation and evoked inflammation in humans. J Nutr Biochem 30:126-32|
|Zhong, Ming; Zhang, Hanrui; Reilly, John P et al. (2015) ABO Blood Group as a Model for Platelet Glycan Modification in Arterial Thrombosis. Arterioscler Thromb Vasc Biol 35:1570-8|
|Bauer, Robert C; Tohyama, Junichiro; Cui, Jian et al. (2015) Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131:1202-13|
|Qamar, Arman; Khetarpal, Sumeet A; Khera, Amit V et al. (2015) Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 35:1880-8|
|Shah, Rachana; O'Neill, Sean M; Hinkle, Christine et al. (2015) Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice. PLoS One 10:e0138317|
|Ferguson, Jane F; Shah, Rhia Y; Shah, Rachana et al. (2015) Activation of innate immunity modulates insulin sensitivity, glucose effectiveness and pancreatic Î²-cell function in both African ancestry and European ancestry healthy humans. Metabolism 64:513-20|
|Zhang, Hanrui; Xue, Chenyi; Shah, Rhia et al. (2015) Functional analysis and transcriptomic profiling of iPSC-derived macrophages and their application in modeling Mendelian disease. Circ Res 117:17-28|
|Ferguson, Jane F; Meyer, Nuala J; Qu, Liming et al. (2015) Integrative genomics identifies 7p11.2 as a novel locus for fever and clinical stress response in humans. Hum Mol Genet 24:1801-12|
|Zhang, Hanrui; Reilly, Muredach P (2015) IRF2BP2: A New Player at the Crossroads of Inflammation and Lipid Metabolism. Circ Res 117:656-8|
Showing the most recent 10 out of 20 publications