Atherosclerosis and its complications such as myocardial infarction and stroke are the leading cause of morbidity and mortality in the U.S., and account for nearly 75% of all deaths from cardiovascular disease (CVD). In addition, chronic kidney disease (CKD) is a common disease affecting as high as 10% of the world's population. CKD causes hyperuremia which are known as severe precondition exacerbating atherosclerosis. Therefore, novel therapies are urgently needed to inhibit the acceleration of atherosclerosis associated with CKD. However, the mechanisms underlying how CKD accelerates atherosclerosis remain poorly defined. We recently reported that caspase-1 (Casp1) activation plays an essential role in sensing metabolic danger signals and initiates inflammation, a condition determines the initiation and progression of atherosclerosis. However, the role of Casp1 signaling in CKD-accelerated atherosclerosis has not been studied. Our preliminary study suggest that Casp1 activation may contribute to CKD-accelerated atherosclerosis. The central hypothesis to be examined in this proposal is that Casp1 activation mediates vessel wall atherogenic cellular pathology in CKD patients and CKD mice, and that Casp1 suppression could rescue CKD-related atherosclerosis. We will examine the effect of CKD on endothelial cell (EC) activation (Yang), inflammatory monocyte (MC) differentiation (Wang), and vascular smooth muscle cell (VSMC) migration/proliferation (Choi) and dissect the underlying mechanism. We will test our hypothesis by using the following three aims:
Aim 1 will examine Casp1 activation in EC, MC, and VSMC in CKD- CVD patients, and CKD-atherosclerosis mice (phenotypic studies).
Aim 2 will examine the mechanisms underlying CKD-induced Casp1 activation and vessel wall cell pathological changes (mechanistic studies).
Aim 3 will determine the causative roles of Casp1-NLRP3 inflammasome on vessel wall cell pathological changes and in mouse CKD-atherosclerosis (therapy/verification studies). Success of this project will lead to the development of novel therapeutics for CKD-related CVD.

Public Health Relevance

Chronic kidney disease (CKD) is a common disease affecting >15% of the US adult population and has cardiovascular mortality10- to 30-folds greater than that in general population. We will examine the contribution and mechanism of caspase-1- inflammasome pathway in CKD-accelerated vascular disease. Success of this study would characterize caspase-1 inflammasome molecular signaling in CKD-accelerated atherosclerosis and lead to the development of new therapeutics for the treatment of CKD-related CVD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fleg, Jerome
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Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
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