Oral-facial-digital syndrome type 1 (OFD1) and polycystic kidney disease (PKD) frequently present together in human patients. The shared pathologies are likely linked to defects in common pathways. OFD1, like a growing list of proteins that are associated with craniofacial and cystic kidney disease, localizes to and functions within the primary cilium. The primary cilium is an antenna-like organelle that is crucia in the regulation of organ development and function. At the cellular level this is due to the mechanosensory and signaling functions of the cilia in regulating cell growth and differentiation. The published literature leads to the hypothesis that OFD1 is targeted to the primary cilium of oral cavity derived odontoblast and renal epithelial cells using a conserved trafficking mechanism where it is organized into membrane microdomains with specialized signaling functions.
Two specific aims are proposed.
Aim 1 will determine the mechanism by which OFD1 is targeted to the primary cilium in odontoblasts and renal epithelia using methodologies that dissect the spatio-temporal transport of OFD1 and evaluate dependence on known ciliary trafficking components for ciliary delivery.
Aim 2 will evaluate the assembly of OFD1 into specialized ciliary signaling domains and membrane protein interactions. The proposed research is the first of its kind to directly compare the ciliary delivery and membrane organization of OFD1 with other key ciliary proteins that when defective result in craniofacial and kidney disorders in the relevant human cell types. The results will provide new information on how proteins are delivered to and functionally organized within this cellular location. The results have relevance to New Mexico's populations where some craniofacial disorders show a significantly higher prevalence possibly due to unique ethnic and genetic factors. The application of novel methodologies for monitoring the spatio-temporal trafficking of ciliary proteins and their assembly into distinct microdomains is expected to validate new and highly quantitative approaches for studying ciliary protein trafficking, organization, and function. Together these contributions are significant because of their potential to determine the commonalities between ciliary proteins in diverse cell types and identify targets that may in the long term be used to develop new therapeutic interventions for enhancing protein targeting to the correct location of the cell.
Oral-facial-digital syndrome type 1 is often accompanied by polycystic kidney disease due to changes in the function of a specialized cell antenna called a primary cilium. Comparisons between tooth and kidney cells will be conducted to determine if these cell types shared a common mechanism for delivering and organizing proteins in the cilium to account for the multiple organ defects. The studies will identify targets that may in the long term be used to develop new therapeutic interventions for enhancing protein delivery to the cilium and thereby normalizing cell function.
| Jerman, Stephanie; Ward, Heather H; Lee, Rebecca et al. (2014) OFD1 and flotillins are integral components of a ciliary signaling protein complex organized by polycystins in renal epithelia and odontoblasts. PLoS One 9:e106330 |
