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LEAD SUPERVISOR:  Dr Zameel Cader, Nuffield Department of clinical neurosciences

Co-supervisor: Dr Sally Cowley, Sir William Dunn School of Pathology

Commercial partner: Eli Lilly

 

The sensory ganglia, containing cell bodies of peripheral sensory neurons, have a key role in both normal sensation and chronic pain conditions. The Cader lab has developed protocols for the generation of human induced pluripotent stem cell (iPSC) derived pain sensory neuron subtypes and satellite glial cells (SGC), which are critical supporting cells. Whilst representing major advances for the field, there is presently no physiological model recapitulating sensory ganglia composition or architecture, limiting the translational relevance of current models. This project will use Cader/Cowley lab know-how and Lilly’s deep expertise in pain, to develop sensory ganglia organoid models to study chronic pain mechanisms and pain target discovery.

Aim 1: Creation of 3D-sensory organoids 

A tri-compartment PDMS mould, with chambers for cells bodies and neuronal outgrowths, will be developed for 3D-printing. Cell culture and extracellular substrate conditions will be optimised and resulting organoids examined by microscopy for recapitulation of sensory ganglia morphology. Molecular characterisation will be undertaken to compare with 2D-cultures and human post-mortem sensory ganglia.

Aim 2: Functional competence of sensory ganglia organoids

Cell function will be analysed using fast calcium imaging using GCaMP reporters, multi-electrode arrays and patch clamp electrophysiology. The responses to a variety of noxious ligands will be assessed and compared with responses in 2D-cultures. The tri-compartment cultures will allow investigation into the fundamental mechanisms of human peripheral sensory transduction.

Aim 3: Investigation of chronic pain mechanisms

iPSC lines from chronic pain patients (e.g. mutations in TRESK and Nav1.7 and patients with painful diabetic neuropathy) as well as ‘gene-corrected’ iPSC will be differentiated into sensory ganglia organoids and functional and molecular phenotype assessed in comparison to 2D-cultures. The model also provides an opportunity to elucidate cross-talk between cell types and their contribution to pain relevant cellular phenotypes. The response to a nerve injury – for example induced by a chemotherapeutic agent, on the functional and molecular response will be examined.

The project addresses MRC priorities of inter-disciplinary (informatics and cell biology) and quantitative (e.g. interpretation of multi-modal electrophysiology data) research. It also address industry priorities in drug discovery.

The project will help establish a strong collaboration between the Cader/Cowley labs and Lilly partners. The academic labs will benefit from the wide breadth of translational research expertise in Pain as well the specific contribution of informatics in the project – learnings that can then be applied to related academic research programmes. Lilly will benefit from improved human cellular models that underpin drug discovery efforts. Mechanistic insights into pain mechanism may lead to nominations for novel targets in the Lilly pain pipeline. Furthermore the training of individuals able to work in academia and industry will help Lilly recruit appropriately skilled staff in the future.

 

Apply using course: DPhil in Clinical Neurosciences

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