Project Details
Projekt
The Origin of Tooth Pain: Linking Polymodal TRP channels on Odontoblasts and Pulp Fibroblasts to Sensory Nerves
Subject Area
Dentistry, Oral Surgery
Anaesthesiology
Anatomy and Physiology
Anaesthesiology
Anatomy and Physiology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 535375124
Worldwide, 2.4 billion people suffer from untreated caries and painful tooth hypersensitivity. Bacterial biofilm-related acidic metabolites demineralize enamel and dentin and induce inflammation in the dental pulp. Acidic reflux-induced erosive damage is another wide-spread problem. Tooth ache due to hypersensitivity is a large problem in the dental clinic, because it can be excruciating and common analgesics are ineffective. In the tooth pulp, a dense network of free nerve endings is in intimate contact with immune cells, dentin-forming odontoblasts and fibroblasts. So far, pain from thermal, mechanical, or biochemical cues was believed to arise from a fluid-dynamic induced mechanosensory process where dentinal tubules act as hydraulic link between the physical stimulus and the nerve terminals at the pulp-dentin boundary. However, our previous research delivered experimental evidence for the odontoblast processes as the transduction site for painful cold via TRPC5 channels. Therefore, Odontoblasts act as primary sensory cells and are the origin of tooth pain. Based on these novel findings, this research project follows three main objectives. We assess the specialized localization and differential function of several TRPC channels, including TRPC1, TRPC3 and TRPC4, across odontoblasts, fibroblast and sensory nerves with reporter and knockout mouse models. Then, we establish an optogenetic mouse model to assess the specific function of Odontoblasts in the origin of tooth pain. This model is based on DMP1-Cre, ChR2 and ArchT mice. We use light to manipulate Odontoblasts through the incisor’s lingual surface where the thinner enamel layer is transparent. This model will be combined with extracellular recordings from jaw-nerve preparations and GCaMP-based intravital calcium imaging in trigeminal ganglia. Last but not least, we will develop vital pulp organoids as critical tools to investigate the intricate interplay between nerve endings, odontoblasts and fibroblasts in situ. We will use the tooth pulps from the optogenetic mouse models to generate organoids on intact dentin and innervated by sensory nerves. These organoids will be characterized for their sensory capacity using optogenetic manipulation, patch clamp recordings and confocal calcium imaging, guided by information from our previously established transcriptomic ion channel and GPCR profile from dental primary afferent neurons. The aim is to obtain a concrete ion channel and signaling molecule profile for the mouse and human tooth pulp. In teeth the functionality and sensory properties of the tooth pulp are the result of an intimate interaction of highly specialized cell types and sensory nerves and their understanding is crucial for novel tooth pain treatment strategies and the future advancement of regenerative endodontic therapies aiming at the restoration of sensory and regenerative function of the dental pulp.
DFG Programme
Research Grants
