Understanding spatiotemporal GPCR signalling in astrocytes using designer receptors and microfluidic technology
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
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Organisations
People |
ORCID iD |
| Nicholas Holliday (Primary Supervisor) |
Publications
Keller M
(2020)
Fluorescence Labeling of Neurotensin(8-13) via Arginine Residues Gives Molecular Tools with High Receptor Affinity.
in ACS medicinal chemistry letters
She X
(2020)
Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor.
in Journal of medicinal chemistry
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M008770/1 | 30/09/2015 | 31/03/2024 | |||
| 1644276 | Studentship | BB/M008770/1 | 30/09/2015 | 29/09/2019 |
| Description | I have now characterised the designer receptor (DREADD) of muscarinic M1. DREADD receptors have been altered to stop the normal ligand binding (ACh) and rather a bioloigcally inert substance (CNO) now bindings. This allows for a system in which there is less non-specific binding and when the cell reacts to CNO, we know that the signalling must only be through the M1 pathway. I have also tested allosteric modulators on this system. Allosteric modulators are drugs which do not bind at the site of the receptor as ACh or CNO would, but they bind the receptor and this alters how ligands signal here. We have found that there is increased M1 signalling with the drug BQCA. We are now going to test this using fluorescent ligands and use competition binding to answer the kinetics of these drugs binding the M1 receptor. I am testing the clozapine derivatives on non-transfected astrocytes as a control in both the calcium imaging assay and stellation. |
| Exploitation Route | All together these results have answered novel questions of receptor-ligand interactions within a temporal and spatial manner and in future work I will delineate how this effects are encoded by cells, and the link to diseases especially using the astrocytes. Ligand occupancy is a hot topic at the moment and there is interest in how this results in different therapeutic outcomes which will have a large societal impact. In vitro studies like mine, can be built on in the drug discovery process and will give novel tools to the science world with DREADD receptors, allosteric modulators and the microfluidic system to carry on with this such research in a highly specific and targeted manner. |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
| URL | http://molpharm.aspetjournals.org/content/molpharm/83/2/521.full.pdf?with-ds=yes |
| Description | My research focuses on looking at the spatiotemporal patterns of ligand-receptor binding and how these aspects alter cell signalling pathways. There is a strong pharmacological link to this project, which means that current and future therapeutics (and the process in which these are made) will benefit from increased knowledge of this area. Improved understanding of this area means that patients may be able to benefit from drugs which have improved design properties, therefore addressing an illness more effectively with less side effects. The links to health and disease from the cellular based project I am undertaking means that there is certainly scope for a large social impact in the future. New cellular tools (such as designer-receptors/optogenetic receptors) will also encourage the use of the three Rs of animal work that is encouraged by the government and ethics groups (as discussed in Anticipated Outputs) due to more specific ligand-receptor binding with fewer side-effects expected. I am also currently using a more novel tool (microfluidic setup) to investigate the kinetics of cell signalling. Once fully characterised a microfluidic setup will have wide-ranging effects on kinetic/cell signalling scientists and how they can add a drug to cells, and expand the questions which are answered within labs, especially involving the non-equilibrium phase of ligand-receptor interactions which is a hot topic at the moment. |
| First Year Of Impact | 2016 |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal Economic Policy & public services |
| Description | UNICAS@Graduate School Inter-disciplinary Sandpit Programme Funding Application |
| Amount | £5,000 (GBP) |
| Organisation | University of Nottingham |
| Department | University of Nottingham Interdisciplinary Centre for Analytical Science (UNICAS) |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 03/2018 |
| End | 06/2018 |