The primary goal of this proposal is to train and bridge the principal investigator toward becoming an independent scientist in the field of cardiovascular pathology with a focus on chronic kidney disease (CKD) and diabetes mellitus. Specifically this program proposes a detailed career development plan and a research plan involving mechanistic studies of vascular cell differentiation and phenotypic modulation in vascular medial calcification, a phenomenon that has been observed in ESRD and diabetic patients. The career development plan includes mentorship, coursework, research training, interaction with the scientific community, and development of leadership and management skills. This will enhance scientific development of the principle investigator in a translational research area of cardiovascular pathology associated with CKD and diabetes mellitus. Vascular medial calcification occurs at high frequency in patients with CKD and type II diabetes mellitus, and is recommended as a strong independent predictor of cardiovascular mortality as well as future events of coronary heart disease, stroke, and lower-lamb amputation in this population. In preliminary experiments, the principle investigator has found that vascular wall cells appear to play a crucial role in mediating vascular calcification where cartilaginous metaplasia and osteochondral tissue is observed. Understanding the origins of the cells participating in osteochondral tissue formation in calcified lesions and the mechanisms controlling the cell differentiation may aid in the development of novel therapeutic strategies to prevent and potentially reverse vascular calcification associated with the CKD and diabetes. To fulfill this goal, the principal investigator has proposed the following three specific aims: 1) to determine origins of osteochondrogenic cells observed in arterial medial calcification using uremic and transgenic mouse models;2) to determine the role of phosphate and calcium in the phenotypic transition of vascular SMCs in vitro and the gene expression profile of osteochondrogenic cells in calcified arterial media;and 3) to determine the requirement and mechanisms of SMC lineage down-regulation and Erk1/2 activity during vascular calcification. The University of Washington represents an outstanding environment for the proposed studies and the development of translational scientists. With the prospective support from the present award, this environment will allow the principal investigator to acquire the technical and critical thinking skills toward a successful career as an independent scientist.
