This application proposes a career development award for a fellow in cardiovascular medicine with scientific interest in defining mechanistic relationships of novel loci for atherosclerosis with relevant in vivo, tissue and cellular phenotypes in humans. We have designed a structured career development plan with a rigorously mentored scientific plan to position the candidate for independent investigation at the end of five years. The broad hypothesis is that a locus detected by genome wide association studies (GWAS) downstream of the CXCL12 gene will be associated with mRNA and protein levels of CXCL12 in human inflammation and in cells of relevance to atherosclerosis. CXCL12 is a unique chemokine with putative anti-inflammatory and anti-atherogenic properties. It is not clear, however, that CXCL12 is the causal gene for the recently replicated GWAS signal. Although CXCL12 expression is constitutive, its regulated expression may be responsible for its role in vascular disease. Thus, genetic modulation of CXCL12 and the atlneroprotective properties may only be unmasked during inflammatory stress. The applicant poses three questions. First, does genetic variation in the CXCL12 region, both (a) the GWAS locus and (b) within the gene itself, associate with plasma levels of CXCL12 and plasma inflammatory risk markers in a community-based study of cardiovascular disease? We have exciting preliminary data that there is a significant association between the GWAS locus and plasma CXCL12 levels. Further study of this will be addressed by using PennCAC, an asymptomatic, community- based sample -2,800 subjects with extensive phenotyping. Second, does genetic variation in the CXCL12 region modulate endotoxemia-evoked adipose mRNA expression, plasma CXCL12 protein levels and inflammatory responses in vivo? This will be addressed through an existing Penn SCCOR resource which uses low-dose human endotoxemia as a model of inflammatory vascular injury. Third, does genetic variation in the CXCL12 region modulate mRNA and protein expression in monocyte-derived macrophages and human skin fibroblasts isolated and cultured ex vivo? This will be addressed by isolating and culturing these cells relevant to atherogenesis ex vivo from subjects with defined genetic variations in CXCL12 region. Thus, the goal of this project is to pursue human translational studies to define the effect of genetic variation in the CXCL12 region on CXCL12 mRNA and protein, at rest, during evoked inflammation in vivo, and in cells and tissues ex vivo.
Myocardial infarction and coronary artery disease clusters within families, and recent development in high- throughput genotyping have yielded promising new pathways in which genetic variation may predispose to the disease states. The goal of this proposal is to perform human and experimental studies of a replicated, strong signal near chemokine gene CXCL12. Our goal is to better characterize and understand the biological and pathophysiological relevance of this novel locus in humans in vivo.
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