Systems biology in physiology: the vasopressin signaling network in kidney

Abstract

Over the past 80 years, physiological research has moved progressively in a reductionist direction, providing mechanistic information on a smaller and smaller scale. This trend has culminated in the present focus on “molecular physiology,” which deals with the function of single molecules responsible for cellular function. There is a need to assemble the information from the molecular level into models that explain physiological function at cellular, tissue, organ, and whole organism levels. Such integration is the major focus of an approach called “systems biology.” The genome sequencing projects provide a basis for a new kind of systems biology called “data-rich” systems biology that is based on large-scale data acquisition methods including protein mass spectrometry, DNA microarrays, and deep sequencing of nucleic acids. These techniques allow investigators to measure thousands of variables simultaneously in response to an external stimulus. My laboratory is applying such an approach to the question: “How does the peptide hormone vasopressin regulate water permeability in the renal collecting duct?” We are using protein mass spectrometry to identify and quantify the phosphoproteome of collecting duct cells. The response to vasopressin, presented in the form of a network model, includes a general downregulation of proline-directed kinases (MAP kinases and cyclin-dependent kinases) and upregulation of basophilic kinases (ACG kinases and calmodulin-dependent kinases). Further progress depends on characterization and localization of candidate protein kinases in these families. The ultimate goal is to use multivariate statistical techniques and differential equations to obtain predictive models describing vasopressin signaling in the renal collecting duct.