Greater Manchester, England, United Kingdom
In 2014, I was awarded a BBSRC David Phillips Fellowship, enabling me to establish an independent programme of research at the Wellcome Centre for Cell-Matrix Research (University of Manchester). My group examines the ‘mechanobiology of ageing’: how the mechanical properties of tissues are matched to their functions, how these properties are maintained by regulation of the extracellular matrix (ECM) and intracellular signalling, and how dysregulation of ECM and mechanotransduction pathways can contribute to pathologies of ageing and disease. We have made important scientific contributions over a range of disciplines: (i) Understanding fundamental aspects of mechanobiology, such as how cells respond to cyclic tensile loading (Blythe, 2019; Gilbert, 2019); (ii) Understanding how senescence affects the regulation of the cellular responses to stimulation, such as heat stress (Llewellyn, 2023) and the mechanical microenvironment (Mallikarjun, 2022); (iii) Understanding fundamental aspects of chronobiology, such as how the ECM is regulated over a circadian cycle (Chang, 2020); (iv) Understanding the role of ECM in age-associated disease processes, such as fibrosis (Herrera, 2019); (v) Bioengineering model systems to mimic aspects of tissue physiology (Lee, 2018); (vi) Development of mass spectrometry proteomics methods to the study of the ECM and signalling processes, with resolution in time and space (Herrera, 2020; Mallikarjun, 2020; Pedley, 2020; Ozols, 2021).
Group Leader in the Manchester Cell-Matrix Centre. Senior Lecturer in the Division of Cell Matrix Biology and Regenerative Medicine. Academic Lead for the Biological Mass Spectrometry (BioMS) Core Facility. Programme Director for the MSc in Tissue Engineering for Regenerative Medicine.
Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but any systematic relationship to specific proteins is poorly understood. We developed mass spectrometry assays to quantify the protein content of tissue, showing that the nucleoskeletal protein lamin-A has characteristics of a ‘biological polymer’, scaling as a function of tissue elasticity. Additional investigation allowed elucidation of the pathways that regulate the lamina: increased lamin-A caused translocation of retinoic acid receptor transcription factors to the nucleus, enhancing lamin-A transcription and thus completing a mechanically sensitive feedback loop. Further regulatory roles were uncovered as decisions of stem cell fate towards fat or bone were respectively enhanced by low or high lamin-A levels. Asking broadly why lamin regulation is important, we might consider a Goldilocks-like appraisal of the consequences of too little or too much lamin-A, and therefore why nature favors a lamin level ‘just right’ for each environment. Low lamin-A allows the nucleus to deform elastically, which is essential for cells such as those in blood that need to squeeze into restricted spaces or migrating cells during development. For similar reasons, we have found that reduced lamin-A can favor metastasis in cancer, but that here extreme deformation can cause apoptosis as the lamina fails in performing its protective role. Diseases relating to the lamin-A gene primarily affect stiff tissue because this is where our cells are most dependent on the protective qualities of lamin-A. The lamina is a central component of the cellular skeleton, and stresses applied to the cell will act on and through the nucleus where mechanical robustness is needed to protect the fragile strands of DNA.