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Molecular and cellular mechanisms of fluid balance in C. elegans

Award Number: R35GM162254
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Molecular and cellular mechanisms of fluid balance in C. elegans - Project Summary Osmolarity measures the concentration of solute particles, which represents a fundamental property of both extra- and intracellular fluids. Since osmolarity affects all biological processes, osmolarity homeostasis is vital for the survival of every living organism, ranging from bacteria to humans. The osmotic reading of human body fluids is continuously monitored in the brain and kept within a very narrow physiological range, 275-295 mOsm/Kg. While a small osmotic fluctuation (1-3%) is tolerable, perturbations larger than these are deleterious to health and can be life-threatening in humans. Thus, robust mechanisms have been evolved to sense and regulate osmolarity. For example, as little as a one percent increase in blood osmolarity is sufficient to trigger thirst, which motivates individuals to find and consume water. However, our understanding of osmolarity sensation and regulation is frustratingly incomplete in animals. At least two major knowledge gaps are presented and greatly hinder our understanding: 1) the molecular identity of most osmosensors (osmolarity-sensing receptors) is still unknown; 2) the cellular mechanisms underlying dehydration selectively motivates animals for rehydration are unclear. Here, we propose to address these two questions in C. elegans. Like mammals, C. elegans has elegant osmolarity sensation and regulation systems, and conserved signaling molecules have been identified. This, together with its fully mapped brain connectome and facile and rich genetic tools, makes C. elegans an ideal system for identifying novel osmosensors and studying neural logic underlying rehydration behaviors. To identify osmosensors in C. elegans, we designed and conducted a neural activity-based genetic screen. We have identified OSGR-1 and OSGR-2 as candidate osmosensors in C. elegans. Despite this exciting finding, many questions remain unanswered. In the current proposal, we propose to characterize the molecular mechanisms by which OSGR-1 and OSGR-2 sense osmolarity. We will test whether OSGR-1/2 are mechanically sensitive and identify the molecular determinants which make OSGR-1/2 osmosensitive. At the cellular level, we will investigate the neural circuits that govern the rehydration behaviors of dehydrated C. elegans. We will take a multidisciplinary approach by integrating molecular genetics, behavioral analysis, calcium imaging, chemo- and opto-genetics, electrophysiology, and cryo-EM. The proposed work will help us identify and characterize novel osmosensors in the animal kingdom, gain a molecular understanding of how osmosensors sense osmotic stimuli, and uncover neural mechanisms underlying rehydration behaviors evoked by internal body fluid imbalance. Successfully accomplishing these projects will greatly enhance our understanding of body fluid homeostasis, a fundamental yet less understood area.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $288,713 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	1	9/7/2026	NEW	$288,713
														Subtotal = $288,713

Grand Total All Awards = $288,713

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Molecular and cellular mechanisms of fluid balance in C. elegans

Award Number: R35GM162254

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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