Juan-Pablo Castillo, Ph.D.

Research

Mechanotransduction is the fundamental biophysical process that underlies the senses of touch, balance, proprioception, and hearing and is mediated by mechanosensitive protein complexes that effectively couple the action of external mechanical forces to the opening of specialized ion channels. In general, how these molecular complexes work remains a mystery, even though the proteins involved have been identified and many of their structures solved. This knowledge gap is largely because of the difficulties in obtaining working quantities of mechanosensory complexes to allow proper biophysical and biochemical characterization at the molecular level. The six touch receptor neurons found in the pioneer nematode C. elegans are an ideal system to study the function of mechanotransduction complexes that enable nematodes to feel and react to gentle touch. Furthermore, we can evaluate critical malfunctions in these complexes that lead to pathological conditions such as neurodegeneration. My research interest consists in studying the molecular mechanism underlying the activity of these mechanotransduction complexes that allow the nematode to perceive and respond to mechanical stimuli. We apply combined tools of genetics, biochemistry, live imaging, electrophysiology, and force spectroscopy to dissect the molecular mechanisms of touch sensation from single molecules to whole animal levels. What are the roles of each protein within the complex? What is their structural arrangement? Are there intracellular and extracellular elements acting on the gating mechanism? What are the minimal components required for assembling functional complexes? Can we rescue defective or damaged complexes? These are some of the questions we aim to tackle. This research is fundamental to help understand the operation of more complex mechanotransduction systems such as the ones found in the skin and inner ear of mammals, which presumably are subject to similar molecular forces and energy landscapes and therefore may share significant aspects in their gating mechanisms.  

As an Innovation Fund investigator, Juan-Pablo Castillo, Ph.D., is teaming up with Eduardo Perozo, Ph.D., to elucidate the molecular principles that underlie mechanotransduction, the process by which mechanical stimuli are translated into electrical signals that can be decoded by the brain. The intricate biochemistry and structural components of the mechanoelectric systems are only partially known and difficult to study. Together, the investigators will leverage recent experimental advances in electrophysiology, force spectroscopy, functional measurements, and cellular engineering to examine this critical process in mechanically active cells, with the goal of visualizing—atom by atom—how transduction occurs. In addition to their shared background in electrophysiology and molecular biophysics, the pair will combine Perozo’s expertise in ion channel structural biology and biochemistry with Castillo’s extensive experience in force spectroscopy and optical instrumentation for this work. They hope these findings will help launch a transformative new period in the field of sensory physiology and lead to deeper understanding of mechanotransduction-based pathologies.