The purpose of this proposal is to foster the development of Wei Chen, MD, MS as an independent translational researcher with the expertise to study vascular calcification (VC) in patients with chronic kidney disease (CKD). CKD patients have a high prevalence of VC, which contributes to their high cardiovascular morbidity and mortality. In part, due to the absence of a valid biomarker for VC, there is currently no effective treatment to slow its progression. Recently, a serum assay was developed to measure calcification propensity, and it may serve as a biomarker for VC to guide development of new therapies. However, it is unknown whether there is a direct relationship between calcification propensity, as measured by this assay, and VC. Dr. Chen will address this question by examining the association of calcification propensity with the severity of VC and the cellular mechanism leading to VC. In conjunction with a biochemist?Dr. Benjamin Miller (advisor), Dr. Chen developed a new, microplate-based assay that uses dynamic light scattering. Their preliminary data demonstrated that the new assay may have a greater predictive power for VC compared to the old assay that used nephelometry. Using the improved assay, Dr. Chen will test the following 2 hypotheses: 1) hemodialysis patients with higher calcification propensity have greater coronary arterial calcification, a faster progression of arterial stiffness and higher all-cause and cardiovascular mortality compared to those with lower propensity; and 2) higher calcification propensity is associated with higher arterial RNA expression of the factors involved in vascular smooth muscle cell osteochondrogenesis, including runt-related transcription factor-2 (runx2) and osteocalcin. The first hypothesis will be tested in 417 patients on hemodialysis from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease study. To test the second hypothesis, Dr. Chen will recruit 100 CKD patients that are undergoing arteriovenous access creation surgeries, measure serum calcification propensity, and obtain intraoperative arterial samples (3-5mm per biopsy per patient) to measure arterial RNA expression of runx2 and osteocalcin. This proposal will make a significant contribution towards validating a novel VC biomarker, provide new insights into the pathophysiology of VC and has the potential to guide new treatment strategies to reduce mortality in patients with CKD. It is innovative because Dr. Chen and her team employ a novel assay and a translational approach to study VC. In addition, this proposal will provide opportunities for Dr. Chen to achieve her training objectives, which are to acquire knowledge and skills in conducting VC research, implementation of Good Clinical Laboratory Practice as well as longitudinal data-analyses and clinical study design. Dr. Chen developed these training objectives with her multidisciplinary mentoring team, and accomplishing these objectives is essential for Dr. Chen to achieve her long-term career goal. This K23 award will support the proposed training and career development activities, and allow Dr. Chen to become an independent translational researcher.
Vascular calcification is prevalent and contributes to high cardiovascular mortality in patients with chronic kidney disease. This research proposal will make a significant contribution towards validating a novel vascular calcification biomarker, provides new insights into the pathophysiology of vascular calcification and has the potential to guide new treatment strategies to reduce mortality in patients with chronic kidney disease, which contributes substantially to the public health burden.
