Using human iPSC-derived sensory neurons to uncover the molecular basis of mechanical hypersensitivity in chronic pain

Mechanical hypersensitivity is a debilitating symptom of many chronic pain conditions and is characterized by painful responses to innocuous mechanical stimuli (e.g., gentle touch, movement). Despite this, the intrinsic cellular, molecular and functional drivers of mechanical hypersensitivity remain poorly understood in humans, in part due to the limited translational success of rodent studies (due to species-specific differences) and limited access to human sensory neurons. As such, there is an urgent need to better understand the molecular contributors of mechanical hypersensitivity in human models that can be exploited for therapeutic intervention. In this fellowship, I will use a panel of patient induced pluripotent stem cell (iPSC)-derived nociceptors to define how mechanical stimuli are detected and transduced and identify the ion channels and modulators (both PIEZO2-specific and independent) that regulate these responses in a human context. This interdisciplinary project builds on my expertise in iPSCs, neuronal differentiation and mechanobiology and leverages Prof. David Bennett’s (Oxford) expertise in pain biology, electrophysiology, patch-sequencing and multimodal omics analysis to:(i) Define the molecular and functional basis of mechanical hypersensitivity: I will establish the mechanism(s) by which human nociceptors respond to mechanical stimuli and how this is dysregulated in monogenic (e.g., Paroxysmal Extreme Pain Disorder) and multifactorial (e.g., Diabetic Peripheral Neuropathy) pain conditions by linking electrophysiological signatures and transcriptomic profiles within single cells.(ii) Identify and characterize PIEZO2-interacting partners in human nociceptors and their contributions to mechanical hypersensitivity.Ultimately, this work will lead to the identification of novel regulators of mechanical hypersensitivity (thus advancing the mechanobiology field) and providing novel pipelines for therapeutic targeting of chronic pain.