Animals use a variety of sensing modalities to interact with their environment, one of which is mechanosensation. Disruptions of this modality in human contribute to sensory disorders as well as hearing disorders. C. elegans is an excellent genetic model system that can be used to identify genes of interest and elucidate neural circuits that are responsible for mechanosensation; there are strong homologies in mechano-electrical transduction channels, synaptic transmission mechanisms, and circuit components. Several additional advantages of C. elegans include the ease of culture, the large number of genetic tools and collection of mutants available for fundamental mechanistic research and drug screens. Current bottlenecks are that quantitative imaging while providing mechanical stimulation to the animals is extremely manual, low throughput, and incompatible with the requirement of large-scale screens. Our long-term objective is to develop technologies and to understand molecular mechanisms and neural circuits that drive mechanosensory responses. The objective of this project is to engineer a micro system for live imaging while stimulating animals mechanically for large-scale screens. This system will not only address the throughput bottleneck but also produce well-controlled standardized stimuli, which overcomes the subjectivity of current manual approaches. In addition to the engineered hardware, we will also develop software to automate the operation as well as extracting quantitative data. We will demonstrate the utility of this technology with two proof-of-concept screens. This project is innovative because it is the first time high-throughput screens can be performed on mechanobiology in vivo. It is significant on both technological and scientific grounds: technologically, this system can be used for many mechanobiology studies, and can be used to screen for therapeutics for diseases involving mechanosensation, which is aligned with our long-term goals; scientifically, this project will produce quantitative understanding in mechanosensation and circuits in mechano-triggered behavior, and specific genes and drug candidates.
Mechanosensation is an important sensory modality; disruptions in normal functions can impact touch, proprioception, and hearing in human. Technologies that enhance the studies of genetic and circuit mechanisms (in assay throughput and sensitivity of the analysis) are important because they may yield molecular targets for drugs and potential therapeutics for these diseases.
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|Cho, Yongmin; Oakland, David N; Lee, Sol Ah et al. (2018) On-chip functional neuroimaging with mechanical stimulation in Caenorhabditis elegans larvae for studying development and neural circuits. Lab Chip 18:601-609|
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|Jackson-Holmes, E L; McDevitt, T C; Lu, H (2017) A microfluidic trap array for longitudinal monitoring and multi-modal phenotypic analysis of individual stem cell aggregates. Lab Chip 17:3634-3642|
|Zhuo, Weipeng; Lu, Hang; McGrath, Patrick T (2017) Microfluidic platform with spatiotemporally controlled micro-environment for studying long-term C. elegans developmental arrests. Lab Chip 17:1826-1833|
|Aubry, G; Lu, H (2017) Droplet array for screening acute behaviour response to chemicals in Caenorhabditis elegans. Lab Chip 17:4303-4311|
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