Biomechanical cues direct cell reprogramming in tissue repair and scarring

All cells are able to recognize and respond to their extracellular environment via surface specific receptors and adhesion molecules. In particular, the biomechanical cues generated by recognition of the extracellular matrix (ECM) are essential in regulating fibroblasts cell behaviour including signal transduction, cytoskeletal organization, migration, proliferation and differentiation. These interactions are critical in maintaining connective tissue homeostasis and crucial during tissue repair. For instance, following injury, alterations in cell-ECM interactions direct fundamental reprogramming of connective tissue fibroblast to orchestrate wound healing and the formation of a scar. Failure to correctly regulate healing and terminate tissue repair leads to excessive scarring and fibrosis, a pathological process associated with many human diseases, including autoimmune-inflammatory disorders, cardiovascular, liver and respiratory diseases and cancer. This project will use cell biology, protein biochemistry and phenotyping with confocal microscopy and flow cytometry to explore the impact of altered ECM and biomechanical cues on fibroblast differentiation and identify key molecular determinants using gene expression profiling (RNASeq), kinome analysis, proteomics and secretomics. In vitro and in vivo models will be used to study the influence of targeting specific biomechanical sensor pathways on fibroblast cell signaling, phenotype and function (myofibroblasts) and on metabolic reprogramming in tissue scarring and fibrosis.

2. References:

1: Ahadome SD, et al ., Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight. 2016 Aug ;1(12):e87001.
2: Heindryckx F, et al., Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med. 2016 Jul 1;8(7):729-44. doi:
3: Ponticos M, et al . , Failed degradation of JunB contributes to overproduction of type I collagen and development of dermal fibrosis in patients with systemic sclerosis. Arthritis Rheumatol. 2015 Jan;67(1):243-53.
4: Shiwen X, et al., Role of myocardin related transcription factor-A (MRTF-A) in scleroderma related fibrosis. PLoS One. 2015 May 8;10(5):e0126015.

Further details on how to apply for this project can be found using the Apply Online button below.

3. Informal enquiry contact details:
Dr M Ponticos ([Email Address Removed])
How to Apply
Please send your covering letter (detailing why you would like to apply) and CV to [Email Address Removed]. Please indicate the project you would like to apply for. More information on the science underpinning this programme can be found at www.qmul.ac.uk/citi/ and www.ucl.ac.uk/flarre.

Deadline for applications: 1st July 2017.

Interviews will be held in the middle of July 2017.