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Supervisors:
Dagan Jenkins and Louise Gregory
Project Description:
Background
The end-point of many diverse pathological states is fibrosis whereby scar tissue is formed. Examples include scars on the skin following wounding, fibrosis in the kidney and liver following cyst formation, fibrosis within the retina causing blindness, as well as myocardial infarction (heart attack). Fibrosis is therefore a fundamental response to tissue damage. It reflects a ‘patch-repair’ process that was probably favoured in evolution to permit survival in emergency situations, but which is imperfect as a long-term physiological solution. Numerous molecular pathways are known to be activated during this fibrotic response but pinpointing which of these mechanisms are causative and which can be targeted therapeutically has proved to be challenging.
Primary cilia are signalling organelles that are present on the surface of most cells in the body. They regulate trafficking of signalling molecules via the process of intraflagellar transport (IFT) which is essential for proper regulation of signal transduction [1]. This requires both IFT motor proteins as well as adaptor proteins (including the BBSome complex) that tethers signalling molecules to IFT proteins [1,2]. We have shown that loss of the BBSome activates fibrotic response pathways [2], and a growing number of other studies have demonstrated that loss of cilia leads to fibrosis [2,3,4].
Aims and Objectives
The overarching purpose of this project is to build on our discovery linking the BBSome to fibrotic signalling pathways [2], and to use IFT genetic models that we have developed and characterised to understand why cilia dysfunction leads to fibrosis. The PhD student doing this project will gain experience in stem cell biology, gene editing, next generation sequencing, computational biology and gene therapy.
Methods
In published work we have generated BBSome and IFT genetic models [1,2], and we have also identified a series of IFT mutations that allow us to carefully control the levels of IFT gene expression and cilia signalling. We will use these mutations to fine-tune the levels of cilia signalling in induced-pluripotent stem cell (iPSC) models of fibrosis.
Aim 1) To validate these models by characterising the mutations, fibrotic gene expression and cellular markers of fibrosis, including use of single-cell RNA sequencing.
Aim 2) To computationally model fibrotic responses in relation to different doses of ciliary function in order to delineate mechanisms of fibrosis.
Aim 3) To test pharmacological inhibition of fibrotic response pathways and genetic therapies targeting IFT for treatment of fibrosis.
Timeline
Year 0-1.5: Characterisation of iPSC models of fibrosis.
Year 1.5-2.5: Computational modelling of fibrotic responses.
Year 1.5-2.5: Testing the therapeutic potential of pharmacological and genetic therapy for fibrosis.
Year 2.5-3: Writing up PhD thesis and results for publication.
Publications
https://profiles.ucl.ac.uk/27156-dagan-jenkins/publications
1) doi: 10.7554/eLife.33067.
2) doi: 10.3390/cells12222662.
3) https://doi.org/10.1038/s41598-024-60298-x
4) https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.028752
Contact Information:
Dagan Jenkins