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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096581-03
Application #
9413367
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gnadt, James W
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
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
Goyal, Yogesh; Levario, Thomas J; Mattingly, Henry H et al. (2017) Parallel imaging of Drosophila embryos for quantitative analysis of genetic perturbations of the Ras pathway. Dis Model Mech 10:923-929
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
Cho, Yongmin; Porto, Daniel A; Hwang, Hyundoo et al. (2017) Automated and controlled mechanical stimulation and functional imaging in vivo in C. elegans. Lab Chip 17:2609-2618
Jackson, E L; Lu, H (2016) Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr Biol (Camb) 8:672-83
Liu, Yi; Lu, Hang (2016) Microfluidics in systems biology-hype or truly useful? Curr Opin Biotechnol 39:215-20
Bates, Kathleen E; Lu, Hang (2016) Optics-Integrated Microfluidic Platforms for Biomolecular Analyses. Biophys J 110:1684-1697