Our somatosensory system detects mechanical stimuli with exquisite sensitivity. We can feel the movement a single hair, discriminate two points on our fingertips with sub-millimeter accuracy, and differentiate changes in vibrational amplitude and frequency over several orders of magnitude. Additionally, our proprioceptors create a dynamic map of our bodies in space through vigilant monitoring of our muscles and tendons. My lab has been focusing on increasing our understanding of the distinct subtypes of mechanosensory neurons that exist, the molecular architecture underlying force transduction, and the physiological roles these molecules and cells play in touch and pain. Mechanosensitive ion channels are key transducers of membrane tension, converting force into electrochemical signals. Piezo2 is one such molecule that is found in sensory neurons, skin, lung and bladder. Despite sharing Piezo2 as a common sensor, the tuning of cells within these tissues to mechanical stimuli can differ dramatically. The sensory neurons that innervate the skin exemplify such specificity in that they are exquisitely tuned to respond to either high or low threshold indentation, hair movement, or vibration. We have been using in vitro and in vivo systems to better understand the function of Piezo2 in mice, specifically determining how the gene is regulated within sensory neurons and delineating the specific roles it is playing in touch and pain. In recent years, great progress as been made researching model organisms. How well these studies translate to humans is an open question. The study of rare inherited conditions offers an alternative approach to gain a window into the genetic underpinnings of human physiology. As part of an ongoing screen of patients with undiagnosed neuromuscular disorders, we are collaborating with Carsten Bonmmann (NINDS) to study patients he has identified with profound but selective deficits in mechanosensation. We are combining exome sequencing, sensory testing, and functional imaging in humans with model systems studies in heterologous cell lines and mice. It is our hope that by doing so we will discovery new disease alleles while better understanding the basic biology that underlies mechanosensation.

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3
Fiscal Year
2016
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Complementary & Integrative Health
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Lam, Ruby M; Chesler, Alexander T (2018) Shear elegance: A novel screen uncovers a mechanosensitive GPCR. J Gen Physiol 150:907-910
Wlaschin, Josette J; Gluski, Jacob M; Nguyen, Eileen et al. (2018) Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury. Elife 7:
Chesler, Alexander T; Szczot, Marcin (2018) Portraits of a pressure sensor. Elife 7:
Szczot, Marcin; Pogorzala, Leah A; Solinski, Hans J├╝rgen et al. (2017) Cell-Type-Specific Splicing of Piezo2 Regulates Mechanotransduction. Cell Rep 21:2760-2771
Ghitani, Nima; Barik, Arnab; Szczot, Marcin et al. (2017) Specialized Mechanosensory Nociceptors Mediating Rapid Responses to Hair Pull. Neuron 95:944-954.e4
Chesler, Alexander T; Szczot, Marcin; Bharucha-Goebel, Diana et al. (2016) The Role of PIEZO2 in Human Mechanosensation. N Engl J Med 375:1355-1364
Le Pichon, Claire E; Chesler, Alexander T (2014) The functional and anatomical dissection of somatosensory subpopulations using mouse genetics. Front Neuroanat 8:21