Projects funded by the National Network but sit outside of individual clusters whilst contributing to a number of our key goals
The Network is also supporting exciting research projects that are of interest across the Clusters. These have the potential to help establish future Clusters and support technology development that will benefit the entire scientific community.
Although mutations and variation that contribute to human disease can be modelled in mouse, as we learn more about disease mechanisms, it is becoming increasingly clear that simple genetically altered mouse models may be of limited use for investigating human pathologies.
We know that genetic variation and mutation that is associated with disease risk often lies within regions of the genome which do not encode proteins. Yet there are limited technologies which allow these non-coding variations to be modelled in vivo.
Similarly, we are learning that the structure of genes plays an important role in their regulation and are identifying human diseases in which structural changes play an important role. Understanding gene regulation at scale necessitates large-scale gene engineering, technologies for which are frequently not routinely available within core facilities.
Establishing simple protocols to allow large regions of the mouse genome to be manipulated would unlock the potential of the mouse for modelling and interrogating all human genetic variation.
Working mainly in mouse embryonic stem cells, we will test, compare and optimize technologies for large scale engineering of genetic loci. Technologies which will be investigated include
In addition, under the remit of horizon scanning, we aim to implement and test newly described technologies to establish whether they provide a robust and reproducible methodology for disease modelling.
Once established and optimized, we hope to deliver a dedicated tool kit of selection cassettes, vector backbones and defined genetic strategies to help disseminate the streamlined protocols to the community.
Working with the network’s research theme clusters, we hope to develop proof-of-concept models which use the developed technology to model complex human disease in the mouse.
This Network Project, led by Prof John Wood of University College London, focuses on the generation and characterisation of mouse mutant lines that can be used by the scientific community to increase and deepen the understanding of pain mechanisms and pathways .It is well established that peripheral sensory neurons play a key role in the majority of pain syndromes, and these cells also interact with the immune system. These cells are the main focus of the pain project.
The work will begin with the generation and characterisation of mice which allow chemogenetic silencing or activation of sets of sensory neurons to analyse cell types involved in different types of pain . A panel of recently characterised Cre lines allow the selective targeting of any or all subsets of sensory neurons. A PSAM-4 silencer mouse has been generated, and is being analysed in detail before release. A PSAM-4 activator mouse will be generated next in collaboration with the MLC. These mice will also be of general interest for neuroimmune studies, unravelling the interaction between the nervous system and immune responses. Behavioural studies are complemented by cellular analysis using genetically encoded calcium indicators in live mice.
Further gene targets are under consideration by the management committee, and include potential human loss-of-pain mutant genes, gain of function mutants that sensitise pain pathways, and candidate pain genes identified in mouse and human genetic studies. Criterion for selection include a broad interest from the network, so that mice will be worked on by more than one, and ideally several groups as well as the broader preclinical pain community. Novel pain assay development, for example measures of spontaneous pain have been developed and are also being characterised mechanistically.
Collaboration with the Network clusters has been established to maximise the potential impact of the project in , for example, studies of cancer pain, and the association between mitochondrial dysfunction and human pain.
Apply for funding opportunities, scientific collaboration and resource sharing all available through the network
