Research

Our research centers on understanding how the nervous system senses external and internal stimuli to produce physiological and behavioral outputs, and how its malfunctions contribute to human diseases. To address this question, we established C. elegans as our animal model system, leveraging multidisciplinary strategies to combine neuorscience approaches, animal behavior recording, genetic screening, metabolomics, biochemistry, biophysics, and structural biology. By using these approaches, we aim to identify receptors, signaling pathways, neural circuits, and inter-tissue communication patterns that drive homeostasis. Furthermore, we also aim to discover the dyshomeostasis mechanisms underlying disease conditions and look for novel targets for treating human patients.

Body Fluid Homeostasis

Animals and humans continuously monitor and regulate body fluid osmolarity to keep it in a narrow physiological range (275-299 mOsm/kg in humans). Abnormal osmolarity is associated with many human diseases: neurodegenerative diseases, cancer, diabetes, cardiovascular diseases, kidney diseases, and dry eye disease. As little as a one persent increase in blood osmolarity is enough to trigger thirst and promote drinking behavior. However, the molecular identities of osmolarity receptors that detect osmolarity changes remain elusive in the animal kingdom. As such, our understanding of osmo-sensation and regulation lags behind, making it one of the least understood sensory modalities. Because of the importance of body fluid homeostasis, animals could evolve redundant mechanisms to regulate body fluid osmolarity, especially at the molecular level. This makes it extremely difficult to identify osmolarity receptors. C. elegans is a powerful model to tackle this problem due to its simplicity, robustness, and rich genetic tools. However, the osmolarity receptors even in worms are still elusive after almost 50 years of searching. We developed a new genetic screening approach to confer the redundancy issues at both cellular and molecular levels in C. elegans, and successfully identified two candidate osmolarity receptors.

Cilia-Independent Functions of Ciliary Proteins

The dysfunction of cilia causes cilia diseases or ciliopathies. More than 30 ciliopathies are affecting about 1 in 2000 individuals, and almost 200 cilia proteins are associated with ciliopathies. Cilia diseases often display a wide spectrum of symptoms and affect several vital tissues, e.g., eyes, kidneys, and the central nervous system. Bardet-Biedl Syndrome (BBS) caused by the BBSome (a cilia protein complex) malfunction is an emblematic cilipathy. Thus, the study of BBS helps to understand other ciliopathies. Vision loss, obesity, learning disability, and renal defect are common symptoms of BBS. Despite the critical roles of the BBSome in transporting signalin molecules inside cilia, it is still unclear how BBS displays those pleiotropic symptoms. Thus far, no cure is available for BBS, however, C. elegans provides us a great opportunity to study the mechanisms underlying BBS. First, C. elegans displays similar symptoms as seen in human patients, including vision loss (C. elegans has no eyes, but still senses light!), obesity, and learning disability. Second, C. elegans has evolutionarily conserved cilia structures. More importantly, C. elegans mutants that can’t develop any cilia are reproducible, which makes it possible to study both cilia-dependent and independent functions of ciliary proteins. Third, we can use whole animal phenotypes, such as vision loss, as our readouts in genetic screenings, instead of studying the BBSome at cellular levels. These unique features make C. elegans an ideal animal model to uncover BBS etiology, which leads to a surpising find that the BBSome can actually regulate photosensation in C. elegans independent of cilia. Furthermore, the downstream mechanisms could be conserved in human cells which involves upregulation of DLK kinase.