Large-Scale Data Integration to Identify Signaling Pathways in Water-Balance Disorders

Water balance disorders occur frequently in hospitalized patients. Most water-balance disorders are due to defects in the regulation of water transport in the kidney collecting duct. Water transport is regulated chiefly through effects of a peptide hormone, vasopressin, on the water channel, aquaporin-2.  Studies in the Knepper Lab employ “Omic” methods (proteomics, phospho-proteomics, RNA sequencing, etc.) to identify the proteins that are involved in the regulation of aquaporin-2 gene transcription by vasopressin.  The signaling process in cells involves regulation of protein phosphorylation through addition and removal of phosphate groups on specific amino acids. Phospho-proteomics studies in the Knepper Lab have identified multiple phosphorylation sites altered in abundance in response to vasopressin. Vasopressin-mediated changes in phosphorylation levels arise from a change in the dynamic balance between the actions of protein kinases (which add phosphate groups) and phosphatases (which remove them). A previous BME student has used Bayesian techniques to identify which of the known 520 protein kinases add phosphate groups at vasopressin-regulated sites (https://pubmed.ncbi.nlm.nih.gov/35659261/). However, the cognate phosphatases that target the same sites remain largely unidentified.  Initial work by other BME students have curated phosphatase catalytic subunits in kidney collecting duct (https://pubmed.ncbi.nlm.nih.gov/27784696/), but phosphatase regulatory subunits remain unexplored. The current student project will aim to use data integration techniques based on application of the same Bayesian algorithm to predict which protein phosphatases (both catalytic cand regulatory subunits) dephosphorylate each vasopressin-regulated phosphorylation site in kidney collecting duct cells. The analysis will  be used to construct a network model of vasopressin-signaling in the renal collecting duct. The resulting work will be published with the BESIP student as first author.