Mechanical force plays pivotal roles in the responses to touch, sound and light, but also to stresses generated in our own body. Specialized sensory cells in our vascular system are periodically deformed with every beat of our heart, yet remain sensitive enough to monitor the mechanical state of our body. Disruption of the sensory capacity of these baroreceptors in our arteries and stretch receptive proprioceptors in our lungs can lead to cardiovascular and pulmonary diseases. Despite this importance to our physiology, the factors contributing to the sense of mechanical force remain elusive due to challenges in studying their consequences on individual cells. Whereas the technology to measure and exert forces on single cells is becoming available, the tools to detect such deformations inside living cells do not yet exist. To investigate the basic mechanotransduction pathways in neurons, this proposal integrates physics, biology, and engineering within the context of the genetic model organism, C. elegans. Of the 302 neurons in C. elegans, 60 are activated by mechanical force. Touch receptor neurons, in particular, are extremely well characterized in terms of their known physiological responses and molecular machinery, and are thus a powerful system to study the cellular response to mechanical stress. Moreover, C. elegans neurons are subjected to cyclic deformation as the animal moves due to the sinusoidal locomotion pattern, analogous to proprioceptive mechanosensors in our own bodies. Importantly, many components of mechano-electrical transduction (MeT) are conserved in mammals. The mentored phase of this project will identify the biochemical force transmission pathway during touch and proprioception that leads to the opening of the MeT channel MEC-2, a conserved protein pivotal to the response to mechanical force in mammals.
Aim 1 will utilize a fluorescent force reporter assay in conjunction with the design and implementation of a novel device to visualize mechanical force effects on MEC-2 in live worms, and Aim 2 will define the interaction of MEC-2 with components of the cellular cytoskeleton using classical biochemistry and genetic screens. These results will show, for the first time, how force gates a eukaryotic MeT channel, relevant to a wide research community in somatosensory neuroscience and hearing. In the long-term, independent phase (Aim 3), this project will aim to understand how mechanical properties of molecules and cells influence decisions of a freely behaving animal and resolve the mechanism of mechanosensation on the molecular, cellular, and systems level. This will involve the characterization of stretch-receptive proprioceptors in C. elegans by calcium imaging of neuron activation, targeted stimulation of isolated proprioceptor culture on elastic substrates and locomotive behavior of transgenic worms carrying modified cytoskeletal proteins. These experiments will be the first that link molecular mechanics to specific behavioral phenotypes such as touch and locomotion.

Public Health Relevance

With every beat of our heart and every breath we take, mechanical forces impact our body. Despite its importance, the ability to sense mechanical stimuli remains elusive;however, understanding how cells sense forces is a necessary first step to understand how embryos form and to develop remedies against diseases where the ability to respond appropriately to mechanical forces is defective, such as hypertension or even heart failure. This research strives to establish a unifying mechanism for how mechanical properties of constituent proteins govern cellular decisions in the peripheral and central nervous system, leading to a greater understanding of how cells, and ultimately our bodies, respond to forces.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K99)
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NST-2 Subcommittee (NST)
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Gnadt, James W
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Stanford University
Schools of Medicine
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