Endothelial cells play an important role in the maintenance of tissue homeostasis. Endothelial dysfunction, characterized by phenotypic and hemodynamic changes in blood vessels, is an early predictor of cardiovascular disease, the leading cause of death worldwide. Chronic oxidant injury to the endothelium during aging leads to endothelial senescence and development of a pro-inflammatory phenotype, increasing the risk of cardiovascular events such as myocardial infarction and stroke. Therefore, better understanding of the molecular mechanisms that regulate vascular aging and inflammation, is essential for the control of cardiovascular disease. The endothelium plays a critical role in inflammation by controlling the expression of cytokines and adhesion molecules involved in attraction, adhesion and infiltration of inflammatory cells. Consistent with the systemic distribution of the vascular network, endothelial cells are a potential source of inflammatory mediators in aging and chronic-inflammatory diseases. Although the identity of pro-inflammatory molecules is well known, the mechanisms that control their expression are complex and multifactorial. Therefore, more studies are needed to identify cellular mediators as well as central molecules and pathways that regulate senescence pro-inflammatory response under normal aging and pathological conditions. Our long-term goal is to develop interventions to preserve endothelial homeostasis, thus preventing vascular inflammation and associated cardiovascular disease. Our goal with the proposed study is to understand how endothelial cMyc regulates vascular aging and inflammation. Recent work from our group have identified a novel role for the transcription factor cMyc as a potential regulator of vascular senescence and inflammation. Our preliminary studies indicate that cMyc expression declines in human endothelial cells undergoing replicative senescence, and that this phenomenon is associated with increased expression of inflammation markers. We performed gene expression profiling studies in mice overexpressing cMyc specifically in endothelial cell lineage and observed a reduction in the expression of the senescence marker p21 and pro-inflammatory mediators with aging in different organs. These findings support the central hypothesis that cMyc is an essential regulator of senescence-associated vascular inflammation. In Aim 1, we will determine how cMyc regulates vascular aging using wild-type and genetically engineered adult mice with conditional deletion of c-Myc specifically in endothelial lineage. In Aim 2, we will investigate the contribution of cMyc to vascular inflammation using the mouse model described in Aim 1. In Aim 3, we will identify cMyc downstream target genes that play a role in vascular aging and inflammation. For the 3 aims proposed, results will be compared to commercially available endothelial cells from young and aged donors. Completion of these aims will define novel mechanisms and potential therapeutic targets that control vascular aging and inflammation.
|Effective start/end date||8/10/17 → 7/31/22|
- National Heart, Lung, and Blood Institute: $31,598.00
- National Heart, Lung, and Blood Institute: $373,050.00
- National Heart, Lung, and Blood Institute: $561,622.00
- National Heart, Lung, and Blood Institute: $383,750.00
- National Heart, Lung, and Blood Institute: $391,475.00
- National Heart, Lung, and Blood Institute: $20,230.00
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