Determination of the mechanisms through which age and disease associated alveolar epithelial matrix changes drive development and progression of pulmonary fibrosis.
Unlike many other matrices, the alveolar ECM is exposed to stretch, with forces increasing. Accumulating evidence point to a critical role for the alveolar basement membrane (BM) in stretch responses, specifically to the importance of laminins (LM) in normal and pathological lung function. It has been shown that LMα 3 expression decreases with and is frequently lost in patients with pulmonary fibrosis, while other LMs expression is dysregulated in scleroderma associated lung fibrosis. Alveolar epithelial cell (AEC) LMα 3 knockout animals display increased fibrosis and mortality in the bleomycin fibrotic but is against overextension in ventilator induced lung injury models. Interestingly, whereas LMs are organized in cloud like arrays in matrix of skin/corneal epithelial cells, in AECs they assembles into fibrillar arrays (figure) and LMα 3 has been shown to stretch signal via a complex containing nidogen, perlecan, and dystroglycan.
To answer these questions this studentship will use in vitro stretch models of alveolar epithelial cells in 2D and 3D culture along with pulmonary fibroblasts along with a variety of cell and molecular approaches. These will include high end techniques such as mass spectroscopy, genome editing, and live cell/molecular imaging modalities including superresolution microscopy and atomic force microscopy.
The student undertaking these studies will benefit from a diverse supervisory team each bringing valuable skills to the project. The studentship will take place primarily in the custom built laboratories of the Institute of Ageing and Chronic Disease at the University which opened in 2016. You will also join a team of scientists investigating different questions relating to pulmonary fibrosis and stretch signalling.
The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.
At minimum applicants should hold or expect to obtain a 1st class or upper second class undergraduate degree or a masters level qualification within biochemistry, molecular or cellular biology disciplines or related fields. Preference will be given to students with extensive lab experience.
Want to know more about the lab/institute:
Lab website: https://spark.adobe.com/page/mXI8W/
Institute Website: https://www.liv.ac.uk/ageing-and-chronic-disease
This is a funded studentship supported by an endowment to the University of Liverpool. This will provide a stipend, fees at the UK/EU rate and a consumables budget
Laminin deposition in the extracellular matrix: a complex picture emerges.
Hamill KJ, Kligys K, Hopkinson SB, Jones JC.
J Cell Sci. 2009 Dec 15;122(Pt 24):4409-17. doi: 10.1242/jcs.041095.
Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.
Morales-Nebreda LI, Rogel MR, Eisenberg JL, Hamill KJ, Soberanes S, Nigdelioglu R, Chi M, Cho T, Radigan KA, Ridge KM, Misharin AV, Woychek A, Hopkinson S, Perlman H, Mutlu GM, Pardo A, Selman M, Jones JC, Budinger GR.
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Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury.
Urich D, Eisenberg JL, Hamill KJ, Takawira D, Chiarella SE, Soberanes S, Gonzalez A, Koentgen F, Manghi T, Hopkinson SB, Misharin AV, Perlman H, Mutlu GM, Budinger GR, Jones JC.
J Cell Sci. 2011 Sep 1;124(Pt 17):2927-37. doi: 10.1242/jcs.080911.