Approximately 9% of the United States population have chronic kidney disease, although, this prevalence is even higher in Veterans given the high prevalence of diabetes and hypertension (underlying causes of CKD) in this patient population. Out of this staggering number, approximately 450,000 patients have end stage renal disease (ESRD) requiring maintenance dialysis. The number of patients with ESRD is expected to increase to 700,000 by 2020. Five year survival for patients on dialysis is about 35%, a rate worse than many cancers. Half of these deaths are attributed to cardiovascular disease (CVD). Therefore, investigations aimed at discovering novel pathways/molecules that can identify patients at high risk for CVD are of vital importance. Furthermore, these pathways can be explored to identify potential targets for therapy. Given the critical role HDL plays in prevention and reversal of CVD, studies aimed at evaluating and improving HDL function in ESRD patients are of considerable clinical and therapeutic value.
End stage renal disease (ESRD) is associated with accelerated atherosclerosis and a marked increase in cardiovascular (CV) mortality. Under normal conditions HDL protects against atherosclerosis via reverse cholesterol transport and potent antioxidant/anti-inflammatory properties (HDL function). It is well established that ESRD is associated with HDL deficiency. In addition, we and other investigators have shown decreased HDL function in patients with ESRD. Recent studies have shown that HDL from patients with ESRD can actually promote inflammation thereby contributing to atherogenesis. Hence, it is no surprise that in patients with ESRD, elevated serum levels of HDL are not always associated with a reduced risk of mortality. These paradoxical findings underscore the need for future studies which focus on deciphering the role of HDL function rather than level in CV mortality. Furthermore, novel signaling pathways need to be identified which can determine HDL function thereby providing prognostic as well as therapeutic tools for future exploration. One novel and promising area which has not been explored to date, is the role of lipid-derived mediators such as endocannabinoids, fatty acid ethanolamides and ceramides in HDL function in ESRD. There is an abundance of evidence implicating these molecules in inflammation, ApolipoproteinA-I/HDL deficiency and CV disease. Therefore, these pathways are promising candidates for evaluation in ESRD. The goal of the applicant is to become an independent translational research investigator. Hence the main training objective of this CDA proposal is to provide him with experience and expertise in clinical and translational research while expanding his knowledge in pathophysiology of lipid-derived mediators. The scientific objectives of this career development award project are four fold. First, to evaluate the role of HDL function in determining the risk of CV and all-cause mortality in patients with ESRD. Second, to determine whether novel lipid-derived mediators can help determine HDL function and mortality. Third, determine the impact of age, gender, race and ethnicity on these measurements. Fourth, in-vitro studies will be performed to evaluate possible utility of FAEs in improving ApoA-I level and HDL function. The proposed application is the first clinical study in a large cohort of dialysis patients which evaluates the role of HDL function in te CV and all cause mortality associated with ESRD. In addition, this is the first clinical study to date that evaluates the association of lipid-derived mediators with HDL dysfunction and CV mortality. Therefore, the findings from this project have a significant potential for identifying prospective new targets for future examination and therapy. To conduct this study, we will be using the serum samples, laboratory and clinical data available from the MADRAD study, a NIDDK-sponsored prospective data-collection study, supported by a K24 and resources of Dr. Kalantar-Zadeh, who is a co-mentor on this application. This CDA project will be conducted in a supportive multi-disciplinary environment with a group of mentors who are renowned experts in different aspects of this proposal. The mentorship and comprehensive training program proposed in this application are designed to build on the training and expertise that the applicant has acquired so far in his career. Furthermore, several future studies based on this novel and promising proposal have been identified which build on the role of HDL function and lipid-derived mediators in CV mortality of the Veterans to be submitted as VA Merit Awards. Hence, the proposed CDA application will not only help advance our knowledge in an area critical to the care of our Veteran's population, it will also prepare and transition the applicant to a career in translational research as an independent investigator in the VA Healthcare System.
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