We have demonstrated that rickets is secondary to impaired hypertrophic chondrocyte apoptosis, and that phosphate ions induce apoptosis of these cells by activating the mitochondrial apoptotic pathway. Erk1/2 phosphorylation by MEK is a key component of this signaling cascade. The studies proposed will identify the role of PTH and PTHrP, vitamin D and bisphosphonates on apoptosis of hypertrophic chondrocytes. Investigations will be performed in vitro in primary chondrocytes, as well as in vivo in genetically engineered mice. These studies will examine the pathway between Erk1/2 phosphorylation and hypertrophic chondrocyte apoptosis. Studies in mice lacking C-Raf in chondrocytes will determine whether this signaling molecule lies upstream of Mek. Studies will also determine whether bisphosphonates modulate hypertrophic chondrocyte apoptosis in response to phosphate, and whether they alter the biomechanical integrity of growing bone. Student may assume the lead for the in vivo or in vitro project, or choose to work with a postdoctoral fellow. Time commitment will be determined by the investment the student is able to make.

Studies in mice and humans demonstrate that the vitamin D receptor is required for cyclic regeneration of the hair follicle. These effects are dependent on DNA binding but not on binding ligand. The cell population in which the VDR is required was shown to be keratinocyte stem cells that are responsible for cyclic regeneration of the hair follicle. The unliganded VDR interacts with effectors of the canonical Wnt signaling pathway and with regulatory regions of genes involved in hedgehog signaling. Studies will be undertaken to identify molecular partners of the VDR as well as downstream targets that are misexpressed in the absence of the VDR. Studies will involve cell models and genetically engineered mice, including VDR and Lef 1 knockout mice, as well as generation of transgenic mice expressing factors that may act downstream of the VDR and rescue the phenotype. Student will interact with postdoctoral fellow and undertake studies in conjunction with them.

Studies will be undertaken in cell and animal models to identify the mechanism by which phosphate ions regulate chondrocyte differentiation during endochondral bone formation and skeletal maturation. In addition to cultures of primary cells and bone explants, studies will be undertaken in genetically altered mice that are models of human disease (XLH), mice with dietary manipulations, and mice with mutations in pathways that are regulated by phosphate. Student will work with a technician and postdoc on an independent project. Previous studies have demonstrated a role for phosphate in the regulation of growth plate maturation, fracture repair and endochondral bone formation.