Ongoing Projects for Students
These ongoing projects may be joined by a new student.
Polycystin Bone and Kidney Project
- We are using Osteocalcin(Oc)-Cre and Dmp1-Cre to generate mouse models that selectively delete Pkd1 and Pkd2 in post-natal osteoblasts and osteocytes. Next, we use microarray or RNA-seq technology to explore the downstream signaling network linking Pkd1 and Pkd2 by using bone mRNAs from control and Oc- or Dmp1-Cre-mediated conditional Pkd1 and Pkd2 null mice.
- We are using Col1a1(3.6)Cre to generate mouse model that selectively delete Pkd2 in post-natal osteoblasts and osteocytes.-mediated conditional deletion of Pkd2 in earlier osteoblastic lineage and investigate the role of Pkd2 in embryonic bone and osteoblast development as well as polycystic kidney disease.
- We continue our collaboration with Dr. Jeremy C. Smith and Dr. Jerome Baudry at Department of Molecular Biophysics, University of Tennessee/Oak Ridge National Laboratory Center to use the knowledge of structure biology in combination with supercomputer in silico calculations to develop novel ligands that target Pkd1 and/or Pkd2.
FGF23 Bone and Kidney Project
- We are using Oc-Cre to delete FGFR1 earlier in the osteoblasts lineage to test the role of FGFR1 signaling in regulating FGF23 and bone phenotypes in both Hyp and Dmp1-/- models. FAM20C null mice have been found to have elevated FGF23.
- We hypothesize that FAM20C deficiency regulates FGF23 indirectly through phosphorylation of Dmp1. We are creating compound mutant Dmp1 and FAM20C mice.
- We hypothesize that hypoxia and oxidative stress are additional regulators of FGF23 and may account for elevations of FGF23 in the setting of chronic kidney disease and other conditions where the renin angiotensin and inflammatory cytokines are elevated. We have found that HIF1α is a major regulator of FGF23 gene transcription in osteoblasts. We plan to explore the biological significance of this finding.
- Similar to FGF23 acting as a counter regulatory hormone for vitamin D with regards to mineral metabolism, we have emerging evidence that FGFG23 acts as a pro-inflammatory factor that counters the beneficial effects of vitamin D on the innate immune/anti-inflammatory response. We will use mouse genetic approaches to confirm this new hypothesis.
- We are collaborating with Dr. Jeremy C. Smith and Dr. Jerome Baudry at Department of Molecular Biophysics, University of Tennessee/Oak Ridge National Laboratory Center to develop novel ligands that target FGF23. We plan to purchase the chemical compounds identified by UTK/ORNL’s initial screen, establish the cell-based functional screening system and test their ability to activate or inhibit FGF23 activation of FGFR1c-αKlotho complex.