Investigating senescence in osteoarthritis

"Cellular senescence has physiological roles in tissue repair and during embryogenesis. Increased senescence however causes tissues dysfunction and directly contributes to disease, including osteoarthritis (OA). Genetic and pharmacological clearance of senescent cells has been shown to alleviate OA pathology in mouse models. These studies suggest that compounds that can kill senescent cells (senolytics) represent novel therapeutic options to treat OA. To develop senolytics, we need a better understanding the biology of senescence in vitro and in vivo.
This project build on our work characterising the mTORC1-autophagy pathway, how it contributes to senescence and represents a targetable vulnerability for senescent cell survival. At present, it is not clear whether the phenotypes we observe in multiple in vitro models of senescence are shared in vivo. The aim of this project is to fully characterise the mTORC1-autophagy pathway in senescence, using in vitro and in vivo models of OA. Determining what a senescent cell 'looks like' at the molecular and cellular level in vivo, how the senescent cell number and specific, defined phenotypes change with OA development, and whether the clearance of senescent cells reduces OA severity.
Objectives:Identify the molecular mechanisms of mTORC1-autophagy dysregulation in senescence
Using multiple musculoskeletal cell culture models of senescence, the student will interrogate the mechanisms regulating mTORC1-autophagy, including the ability to sense mitogenic signals such as growth factors involved in musculoskeletal function and regeneration e.g. TGFSS. Genes implicated in OA risk, identified by collaborators in population health will be knocked out using CRISPR/Cas9 and followed up by characterisation of senescence.
A variety of standard molecular cell biology techniques including cell culture, qPCR, Western blot and immunofluorescence microscopy will be utilised.
Characterise senescence in vivo
Immunohistochemical...