Sorting-out the skeleton: The role of sorting nexins in skeletal health and disease
Understanding the proteins of debilitating bone disease
Sorting nexins (SNXs) are a family of structurally and functional diverse proteins with various roles in intracellular cargo transport and cell signalling. An increasing number of SNXs have been implicated in human diseases including neurological disorders, cancer, inflammation and disorders of bone and mineral metabolism, and therefore represent attractive therapeutic targets.
This project is funded by the National Health and Medical Research Council and examines the role of sorting-nexin 27 (SNX27), a protein crucially involved in the regulation and trafficking of transmembrane cargo, in skeletal growth and homeostasis.
Skeletal growth and remodelling depends upon the strict regulation of bone matrix deposition and resorption.
Central to the activities of skeletal resident cells (for example, osteoblasts) is their ability to respond to growth stimuli, which are achieved via cell-surface proteins cargo (signalling receptors, ion channels and nutrient transporters). Disruptions in cargo-trafficking manifest in several significant disorders of bone and mineral metabolism. However, the molecular participants orchestrating the sorting and recycling of cell-surface cargo in skeletal resident cells remains unclear
Using a combination of genetic mouse models, cell biology and high-resolution optical microscopy we aim to understand the mechanisms of action of SNXs in skeletal resident cells and how they contribute to skeletal homeostasis and disease in an effort to determine their potential for therapeutic development.
Research team lead: Associate Professor Nathan Pavlos
The proposed studies aim to define the precise physiological contribution of SNX27 in skeletal development and disease and yield novel mechanistic insights into the molecular regulation of vital cell-surface signalling cargo, such as the parathyroid hormone receptor (PTHR1), a prominent target of clinical application for human bone and mineral diseases.
Collaboration and funding
Together with Professor Rohan Teasdale and Professor Brett Collins (Institute for Molecular Bioscience, University of Queensland), and Professor Wanjin Hong (Institute for Molecular and Cell Biology, A*STAR, Singapore), we are attempting to define the nature and number of transmembrane signalling cargo regulated by the SNX27-retromer trafficking complex and understand how disruption of these molecular interactions influence skeletal cell function and bone homeostasis.
- The University of Queensland (Institute for Molecular Bioscience and School of Biomedical Sciences)
- A*STAR (Institute for Molecular and Cell Biology)
- National Health and Medical Research Council- Project Grant (APP1078280)
- Western Australia Department of Health- Merit Award (RA/1/85/189)
- UWA-UQ Partnership Research Collaboration Award- (RA/1/1526/129)