Project Summary/Abstract Salt-Inducible Kinases (SIKs) were previously identified as the downstream mediators of PTH receptor signaling in osteocytes in Dr. Yoon’s mentor’s (Dr. Marc Wein) work. Similarly, Dr. Yoon recently reported that PTH receptor signaling suppresses SIKs to induce Cyp27b1 (vitamin D activating enzyme) expression in kidney to promote 1,25-vitamin D (active form of vitamin D) synthesis. To build on these findings, this project will investigate the role of SIKs in PTH-induced Cyp24a1 reduction in kidney. Together with previous findings, this work will demonstrate a novel pathway of how parathyroid hormone (PTH) regulates 1,25-vitamin D. This aim will involve in-depth bioinformatics training with Dr. Mark Meyer on ChIP-sequencing analysis to identify genomic location(s) where transcription factors bind to regulate Cyp24a1 in response to PTH or SIK inhibition. Based on these studies, Dr. Yoon will evaluate the therapeutic potential of SIK inhibition in MBDs with insufficient 1,25-vitamin D levels and compromised bone health: chronic kidney disease mineral and bone disorder (CKD-MBD) and hypoparathyroidism (hypoPT). CKD-MBD has complex pathophysiology with high phosphate and FGF23 levels, secondary hyper-PT yet blunted PTH actions (resulting in low 1,25-vitamin D) due to PTH-resistance. Here, it is hypothesized that targeting SIKs, PTH downstream mediators, will bypass PTH-resistance, which could occur due to abnormalities at the receptor level, and bring PTH-like effects in CKD-MBD by increasing 1,25-vitamin D synthesis and bone formation. These dual benefits of SIK inhibition will shift the paradigm of how we approach CKD-MBD. Likewise, we also hypothesize that SIK inhibitor will increase serum calcium and improve bone health and biomechanical properties in parathyroidectomized mice via stimulating 1,25-vitamin D and bone turnover. Because there are no effective treatments which can improve both mineral metabolism and bone health in these MBDs, this study will suggest a novel target in such diseases. Dr. Yoon will acquire mouse surgery skills to create hypo-PT mouse model with co-mentor Dr. Michael Mannstadt. Moreover, Dr. Yoon will work with Dr. Harald Jueppner on integrative analysis of mineral metabolism parameters in both translational studies. These studies will advance knowledge and provide robust training opportunities in the fields on gene regulation, CKD-MBD, and hypoparathyroidism from a skilled team of experienced mentors. Overall, this career development award will help Dr. Yoon to achieve her ultimate career goal, to explore molecular mechanisms between mineral and bone metabolism regulating factors and hormones in physiological and pathological states.