All cells decode information from their surroundings via receptor molecules, which are proteins that detect these cues and initiate signaling to alter cellular function. Sensory nerves are specialists of this process; they detect the properties of both external and internal environments, translating and relaying this information to alter the behaviour of an entire organism. Sensory input in these nerves is translated into a frequency-coded train of action potentials, which is then relayed to the central nervous system. There are many different flavours of sensory nerves, expressing different combinations of genes that determine their sensitivity and response profile. The identity of many of the genes controlling these features is still unknown, their potential as targets for therapeutic intervention as yet untapped. We conduct experiments to identify and characterise these receptors, their downstream targets and their involvement in sensory function. These efforts will contribute to our understanding of how these neurons function, as well as how these processes are derailed to result in chronic pain conditions. Our experiments that harness the logic of evolution to find such new receptors. We induce random changes in the genome, combined with an unbiased selection process, to give rise to rare emergent phenotypes which can be used to identify novel genes and signaling pathways.
Molecular Receptors of pain
We study ion channels and GPCR-s that decode noxious physical and chemical cues from the environment in primary sensory neurons using a combination of electrophysiology, fluorescent imaging and molecular biology. Our aim is to identify target proteins and signaling pathways that allow intercepting painful stimuli at the level of the periphery.
Receptor molecules that enable primary sensory neurons to respond to noxious stimuli are prime targets for next-generation analgesic therapy. Intercepting the pain signal at this level promises both relative safety and efficacy. The prevalence of chronic pain conditions, and the addictive potential of opioids make this research goal a high priority. We use patch clamp electrophysiology combined with fluorescent imaging techniques and molecular biology approaches to study the regulation of receptors and ion channels that are crucial for the detection of sensory stimuli in primary sensory neurons of Dorsal Root Ganglia (DRG). We are interested in receptors of extreme temperature and mechanical stimuli, as well as natural compounds that elicit complex sensory phenomena.
Gene identification by targeted cellular evolution
We use random genome-wide mutagenesis approaches in an effort to identify new molecules and pathways in a host of different biological fields. We combine genome engineering with highly sensitive and specific selection procedures to enrich cells with rare emergent cellular phenotypes in an effort to identify their genetic underpinning.
Coupling cellular function to its genetic underpinning is a challenging task. We design experiments that harness the logic of evolution to achieve this goal. We use genome editing tools to induce random changes in the genetic makeup of cells, occasionally giving rise to rare emergent cellular phenotypes. We then conduct an unbiased selection process that allows us to enrich these rare cells and study their genetic makeup. We use this approach to uncover the identity of molecular receptors in a wide variety of biological fields, followed by expression profiling and functional testing (using fluorescent imaging and electrophysiology) in heterologous systems and transgenic animal models.
Mechanosensors in proprioceptive neurons
Proprioceptive neurons signal positional cues of limbs and torso to the brain, making complex, coordinated movements possible. The mechano-sensitive ion channel Piezo2 is the principal mechanical receptor in proprioceptive neurons enabling this critical function. See Publications
The mechanosensitive ion channel Piezo2 plays a critical role in somatosensory function. This channel allows not only the detection of innocuous touch, but is also expressed in nerves that detect the state and change of muscle and tendon stretch. The latter neurons conveys positional information to the central nervous system, which is critical for the precise execution of complex movements. With the help of these neurons we can maintain posture and execute tasks even without visual feedback. Lack of Piezo2 leads to loss of such coordination both in both mice and humans.
Mechanotransduction in red blood cells
Red blood cells are exposed to various kinds of mechanical agitation in the vasculature. Mechanosensitive Piezo1 proteins allow these cells to detect and adapt to these forces, enabling them to squeeze through very narrow passages. Piezo1-dependent volume regulation is also a fascinating new factor in malarial susceptibility. See Publications
Red blood cells squeeze through capillaries whose diameter is often smaller than that of the RBC itself. Passage through such narrow vasculature conveys mechanical stress on the RBC, which triggers an active signaling cascade to initiate the loss of a small amount of volume, facilitating erythrocyte passage through the smallest of capillaries. This signaling is initiated by the mechanosensitive ion channel Piezo1. Calcium entry through this channel activates “Gárdos” calcium-activated potassium channels, triggering cell dehydration driven by potassium and chloride efflux from the cell. Gain of function mutations of Piezo1 lead to a clinically benign condition of mildly reduced RBC size. Interestingly, some of these variants also convey resistance to malarial infection, putting Piezo1 on the map of potential targets for treatment of this disease.