Grant: Master's Award: Canada Graduate Scholarships

Secondary hyperparathyroidism (SHPT), a pathological rise in circulating parathyroid hormone (PTH), is a complication and independent risk factor for cardiovascular disease and death in chronic kidney disease (CKD). Clinically, vitamin D-based treatments are used to try to control SHPT; however, 20-30% of patients with SHPT become resistant to these treatments, thereby putting patients at risk for advancing disease. The mechanisms underlying this resistance are incompletely understood, but are thought to be parathyroid-specific. In the proposed research, we will investigate vitamin D precursors that are bound to vitamin D-binding protein (DBP) to gain access to the parathyroid gland cells via megalin-mediated internalization. Although maladaptive changes in renal megalin expression and function are known to lead to dysregulated vitamin D metabolism in the kidney, at least in part, no studies have directly investigated its role in vitamin D metabolism in the parathyroid gland, especially in CKD. This study seeks to determine whether changes in megalin function play a key role in dysregulated parathyroid vitamin D metabolism in a CKD rat model. It is hypothesized that CKD produces a reduction in parathyroid megalin levels such that the uptake of vitamin D into the parathyroid is blunted, and the loss of control of PTH is exacerbated. Megalin mRNA and protein will be measured in parathyroid glands, and an ex-vivo parathyroid culture will be used to perform fluorescence-based assays to evaluate megalin-mediated uptake. This study will provide mechanistic insight towards vitamin D resistance while highlighting megalin as a potential pharmacologic target to ensure effective treatment of SHPT.