This project investigates how localized, membrane-proximal hydrogen peroxide signals regulate redox-sensitive TRP channels and thereby control neuronal and cardiac excitability. Using patch-clamp electrophysiology combined with light-activated materials to generate precisely timed oxidative stimuli, it quantifies how ROS modulate ion channel gating and action potential dynamics in real time. The aim is to define how oxidative stress is translated into pathological hyperexcitability, contributing to pain sensation and cardiac arrhythmias.
Project Details
Background:
Living cells in the brain and the heart communicate through electrical signals. These signals determine whether neurons fire action potentials or whether heart cells beat in a stable rhythm. In many diseases, including chronic pain, neurodegeneration and cardiac arrhythmias, this electrical activity becomes unstable. A major driver of this instability is oxidative stress, in particular short-lived bursts of reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) that arise during inflammation, metabolic stress or tissue damage.
Today it is becoming clear that ROS are not only harmful byproducts but also act as important signaling molecules that directly regulate ion channels in the cell membrane. Among the most important of these are TRP channels, which are present in both neurons and cardiomyocytes. When TRP channels are modulated by oxidative signals, they can push cells into a hyperexcitable state associated with pain or arrhythmias, or into a suppressed state associated with fatigue and failure of normal signaling.
Despite their importance, it is still poorly understood how oxidative signals control TRP channels in a precise and time-dependent manner, and how this translates into changes in the electrical behavior of cells. One major reason is that it has so far been challenging to generate well-controlled oxidative signals at exactly the place where ion channels operate, namely the cell membrane.
Hypothesis and Objectives:
The central idea of this project is that short, localized oxidative signals act as switches that determine whether TRP channels are turned on or off, and thereby decide how excitable a neuron or a heart cell becomes. The objective of this PhD project is to understand how the timing and strength of membrane-proximal H₂O₂ signals control TRP channel function and how this, in turn, shapes electrical activity in neuronal and cardiac cells. By uncovering these relationships, the project aims to explain how oxidative stress is converted into altered firing patterns in nerves and disturbed rhythm in the heart.
Methodology:
The project will combine modern electrophysiology with light-responsive semiconductor materials to study living cells at the level of single ion channels and action potentials. Neurons and cardiac cells will be grown in the laboratory and their electrical activity will be measured using patch-clamp techniques, which allow direct recording of ion channel currents and action potentials with high precision.
To control oxidative signaling, special light-sensitive materials will be used that generate small, localized amounts of hydrogen peroxide when illuminated. This makes it possible to trigger oxidative signals exactly at the cell membrane and to vary their timing and intensity in a highly controlled way. By applying these light-induced oxidative signals while recording electrical activity, the project will directly observe how TRP channels and cellular excitability respond in real time.
The resulting data will reveal how oxidative signals shift cells between normal activity, hypersensitivity and electrical instability. These experimental findings will then be used to build simplified computational models that predict how oxidative stress can lead to pain or arrhythmias, providing a bridge from fundamental cell biology to clinically relevant disease mechanisms.
People Involved
Primary supervisor: Tony Schmidt
Collaborators: Rainer Schindl, Jordi Heijman, Corina Madreiter-Sokolowski