This work proposes a fully integrated approach to the study of mechano-electrical transduction in the sense of touch and focuses on the development of a novel microsystems-based tool?namely, a force clamp that uses appropriately-scaled piezeoresistive cantilevers as direct force sensors (PR force clamp). The proposal includes work to fully characterize the capabilities of a first-generation device, to design and build a second- generation device capable of operating at higher bandwidth, and to use these devices to analyze and model the biomechanics offeree transfer and mechano-electrical transduction by a model mechahoreceptor cell, the touch receptor neurons that innervate the body wall of the nematode Caenorhabditis elegans. C. elegans is an excellent biological platform for developing the proposed tools, which are likely to find application in the study of mechano-electrical transduction in other mechanosensory cells including vertebrate hair cells and dorsal root ganglion. A set of only six touch receptor neurons is responsible for behavioral responses to touch in C. elegans (compared to tens of thousands in vertebrates) and such responses are initiated by activation of the MEC-4 channel complex by forces applied to the body wall. Prototype force clamp systems use PR force clamps and piezoelectric actuators with programmable controllers to apply calibrated nano- to micro-Newton point load profiles with > 1kHz bandwidth. A critical and innovative aspect of this work is the integration of the PR force clamp with patch-clamp electrophysiology for synchronous force-displacement- physiological recordings. This technology will enable the first direct measurement of dynamic changes in tissue stiffness that may occur during mechano-electrical transduction and give rise to adaptation. Relevance to public health. The sense of touch can be degraded by both inherited and acquired disease, including AIDS and diabetes, as well as by chemotherapeutic drugs. Complications from such peripheral sensory neuropathies are estimated to cost more than $4 billion annual in health care costs. Despite this, the sense of touch and its degradation in disease remain poorly understood. The research tools developed in the course of this work have the potential to significantly advance our understanding.
| Kim, Anna A; Nekimken, Adam L; Fechner, Sylvia et al. (2018) Microfluidics for mechanobiology of model organisms. Methods Cell Biol 146:217-259 |
| Mazzochette, E A; Nekimken, A L; Loizeau, F et al. (2018) The tactile receptive fields of freely moving Caenorhabditis elegans nematodes. Integr Biol (Camb) 10:450-463 |
| Fehlauer, Holger; Nekimken, Adam L; Kim, Anna A et al. (2018) Using a Microfluidics Device for Mechanical Stimulation and High Resolution Imaging of C. elegans. J Vis Exp : |
| Ribeiro, Alexandre J S; Schwab, Olivier; Mandegar, Mohammad A et al. (2017) Multi-Imaging Method to Assay the Contractile Mechanical Output of Micropatterned Human iPSC-Derived Cardiac Myocytes. Circ Res 120:1572-1583 |
| Larsen, T; Doll, J C; Loizeau, F et al. (2017) Rise Time Reduction of Thermal Actuators Operated in Air and Water through Optimized Pre-Shaped Open-Loop Driving. J Micromech Microeng 27: |
| Nekimken, Adam L; Mazzochette, Eileen A; Goodman, Miriam B et al. (2017) Forces applied during classical touch assays for Caenorhabditis elegans. PLoS One 12:e0178080 |
| Nekimken, Adam L; Fehlauer, Holger; Kim, Anna A et al. (2017) Pneumatic stimulation of C. elegans mechanoreceptor neurons in a microfluidic trap. Lab Chip 17:1116-1127 |
| Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S et al. (2016) Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis. Cell 167:1734-1749.e22 |
| Ribeiro, Alexandre J S; Denisin, Aleksandra K; Wilson, Robin E et al. (2016) For whom the cells pull: Hydrogel and micropost devices for measuring traction forces. Methods 94:51-64 |
| Paluch, Ewa K; Nelson, Celeste M; Biais, Nicolas et al. (2015) Mechanotransduction: use the force(s). BMC Biol 13:47 |
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