MSc by Research: Systems-level approaches to understanding mechanisms of cellular senescence and aging

About the Project

Age-associated physiological decline is characterized by loss of resilience towards stress and injury. Understanding mechanisms of resilience is a global challenge due to the demographic shift towards aging populations. Cellular senescence is a clinically important phenotype that is both pro-aging and tumor suppressive. Senescence is fundamentally characterized by durable cell cycle arrest in response to replicative aging and cellular stresses. This phenotype was originally described in primary fibroblast cells, which cease proliferation after prolonged culture in vitro. However, it is now recognized that many cell types senesce in response to various cellular insults, including DNA damage and oncogene activation. Understanding mechanisms that promote cellular senescence will be key to identifying approaches to prevent, reverse or eliminate senescent phenotypes.

The Ly laboratory identified a novel ‘cell overgrowth’ mechanism that promotes senescent phenotypes. In response to cell cycle arrest, continued cell size increases results in cell overgrowth and imbalanced scaling of the cell proteome resulting in a cellular stress response and ultimately senescence. This imbalanced proteome scaling is characterized by altered ratios of cell organelles and major changes in the bulk physicochemical properties of the proteome. Senescent phenotypes can be reversed by inhibiting cell growth, indicating that the cell overgrowth is the cause.

While senescent cells are nearly universally dysmorphic, their cell size can either be smaller or larger than the parental non-senescent cell. Indeed, we have discovered genetic perturbations resulting in senescent cells with decreased cell size. We hypothesize that imbalanced proteome scaling occurs in both aberrantly small and large senescent cells, and it is the aberrant scaling, not size per se, that promotes senescence. If true, this would be a unifying mechanism of cellular senescence. To test this hypothesis, the Masters project will unpick the mechanisms linking aberrant size and cellular senescence using genetically tractable in vitro models, advanced proteomic technologies and data analysis pipelines for the interpretation of large datasets.

Specific aims:

1. Generate novel in vitro epithelial models of cellular senescence using genome editing
2. Apply cutting edge proteomics technologies enabled by state-of-the-art mass spectrometry instrumentation to characterize proteome scaling in senescent cells
3. Use CRISPR/Cas9 and inducible protein degradation to interrogate mechanisms of cellular senescence

The expected impacts of this research will support the identification of pathways that can be further explored as targets to prevent or reverse senescent phenotypes. The results will potentially reveal a unifying mechanism linking aberrant cell size regulation and senescence.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.