Project Summary
The ability to sense osmolarity changes and maintain fluid osmolarity is required for normal physiological
functions of every single cell and thus vital for human health. Fluid imbalance, caused by high osmolarity
(hyperosmolarity) or low osmolarity (hypoosmolarity), can lead to irreversible damage to organs and cause
lethal neurological trauma. In humans, the osmolarity of body fluids is continuously monitored in the brain and
kept within a very narrow range (275-299 mOsm/kg). As little as a one percent increase in blood osmolarity is
enough to trigger thirst. A key element for such robust osmoregulation is the molecular osmosensors that
detect osmolarity changes. However, the molecular identities of osmosensors in the animal kingdom have
remained elusive. The difficulty in identifying osmosensors in animals is partly due to the lack of an unbiased
screening system. Previous efforts to identify osmosensors in animals were restricted to TRP channels.
However, osmosensors do not necessarily fall into the TRP channel family and thus may have eluded
detection. The nematode C. elegans is an ideal model to study osmosensing. Like mammals, C. elegans has
osmosensing systems, and conserved signaling molecules have been identified. This, together with its short
generation time (~3 days) and facile and rich genetic tools, makes C. elegans an ideal system for identifying
novel osmosensors. To identify osmosensors in C. elegans, we designed and conducted a neural activity-
based genetic screen. We have identified OSMS-1 and OSMS-2 as candidate osmosensors in C. elegans.
Despite this exciting finding, many questions remain unanswered. In the current proposal, we propose to test
the hypothesis that OSMS-1 and OSMS-2 are bona fide osmosensors and characterize the molecular
mechanisms by which OSMS-1 and OSMS-2 sense osmolarity. We will take a multidisciplinary approach by
integrating molecular genetics, behavioral analysis, calcium imaging, electrophysiology, and cryo-EM. To do
so, I will receive extensive training on calcium imaging, cell culture, electrophysiological recording, and cryo-
EM. The K99/R00 award will allow me to acquire these skills with guidance from my mentors Drs. Shawn Xu
and Melanie Ohi, which will help me to launch an independent research career. The proposed work will lead to
the identification of the first osmosensors in the animal kingdom, gain a molecular understanding of how
osmosensors sense osmotic stimuli, and provide novel insights into osmosensation, osmoregulation and
related human diseases.