Integrative physiology of the organismal osmotic stress response

Osmotic homeostasis is the most aggressively defended physiological setpoint in biology. This is because disruptions in cell volume alter essential physiological parameters, such as macromolecular crowding, ion concentrations, and membrane integrity, all of which are required for cellular function. Disruptions in cell volume are an important pathological feature of many acute and chronic human diseases, such as stroke, diabetes, hypertension, and kidney disease. Much of our understanding of the molecular mechanisms of osmoregulation is derived from cellular models, such as yeast and cultured mammalian cells. A major challenge to the field has been the difficulty in studying this process in a multicellular in vivo setting, where complex neuronal, endocrine, and extracellular matrix interactions, that are not present in cellular models, are preserved. Such questions can be addressed using a simple animal model system. C. elegans exhibits robust behavioral and physiological responses to osmotic stress. Understanding mechanisms of organismal osmoregulation in C. elegans will inform our understanding of human physiology and disease pathophysiology and could reveal novel methods to control pathogenic nematodes. The important and broad questions that we will address include: 1) How do lysosomes detect osmotic stress and signal specific gene expression programs? 2) What is the genetic architecture of pathways controlling organismal osmoregulatory physiology? 3) What are the interoceptive mechanisms that link changes in osmoregulatory physiological state to alterations in nervous system function? Over the last, 20 years, my lab has pioneered the study of osmotic homeostasis in C. elegans. Thanks to advances in CRISPR genome modification, whole-genome resequencing, automated behavioral analysis, and neuronal imaging and optogenetic stimulation, along with new molecular insights gained in the previous funding period, we are uniquely poised to define the integrative physiology of metazoan osmoregulation in unprecedented detail. Project Number: 1R35GM164189-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: SAMUEL LAMITINA | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $501,385 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-J (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11329843