1. On-going Research Studies in the Rosenfeld Lab *The role of RANK/RANKL in vascular complications of chronic kidney disease Effects of air pollution (diesel exhaust) on oxidation of lung phospholipids and the functional properties of HDL Effects of in-utero exposure to diesel exhaust on atherosclerosis in adulthood Studies of Chlamydia pneumoniae persistence in vascular cells

2. It is now estimated that over 15% of the population of the United States have chronic kidney disease (2009 US Renal Data System Annual Data Report). Chronic kidney disease (CKD) patients, especially those on dialysis, have up to a 20-fold increase in cardiovascular disease (CVD) mortality compared with the general population. According to the American Heart Association, end stage renal disease (ESRD) patients are at the highest risk for CVD. Traditional risk factors such as lipids and hypertension fail to explain this increased risk. Currently, there are no therapeutic options for reducing the risk of CVD mortality. CKD is associated with abnormalities in calcium and phosphate metabolism, oxidative stress, and an inflammatory syndrome that together may drive the accelerated atherosclerosis and vascular calcification observed in ESRD disease patients.

3. We have identified the receptor activator of NFkB (RANK)/receptor activator of NFkB ligand (RANKL)/osteoprotegerin (OPG) system as a potential mediator of accelerated atherosclerosis and vascular calcification in CKD. OPG is a decoy receptor for RANKL and its binding with RANKL leads to decreased signaling through the membrane receptor, RANK. OPG deficiency in mice accelerates the development of highly calcified atherosclerotic lesions, and leads to severe osteoporosis, both hallmarks of ESRD in humans.

4. Increased Calcification of Atherosclerotic Plaques in OPG-/- x Apo E-/-

6. Aim 1: To determine the role of RANK/RANKL in the acceleration of atherosclerosis and vascular calcification in a mouse model of CKD. Hypothesis: Uremia induced secretion of RANKL by vascular cells stimulates RANK signaling and the activation of macrophages resulting in increased atherosclerosis and vascular calcification in CKD. Aim 2: To determine the molecular pathways induced by CKD and by RANKL treatment of macrophages. Hypothesis 1: There are specific pathways defined by the spectrum of expressed genes and shed and secreted proteins that are induced by CKD in macrophages and contribute significantly to the accelerated development of atherosclerosis and vascular calcification in CKD. Hypothesis 2: Many of the expressed genes and shed and secreted proteins induced by CKD in macrophages will be comparable to the spectrum of genes and shed and secreted proteins induced by treatment with RANKL.