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Title: Measurement and mathematical modelling of endoplasmic reticulum stress in human adipocytes
Author: Murphy, Alice M.
ISNI:       0000 0004 7972 4246
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2018
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Obesity is the single biggest risk factor for type 2 diabetes mellitus (T2DM). Weight gain chronically induces endoplasmic reticulum (ER) stress in adipocytes, which activates the unfolded protein response (UPR) and leads to inflammation and insulin resistance. Therefore, investigating ways to combat inflammation through ER stress may reduce obesity mediated T2DM. One candidate to improve metabolic health may be cruciferous vegetables, such as broccoli, known to reduce inflammation and the risk of various cancers. Mathematical modelling may be a useful tool in order to identify how time and other factors may impact the UPR, however little experimental time series data exist to support the parameterisation and validation process. The aim was therefore to determine whether perturbation of human adipocytes with tunicamycin and broccoli extract can lead to significant changes in the UPR over time, deriving a novel mathematical model to characterise the relevant components of the UPR. Chub-S7 pre-adipocyte cells were grown, differentiated and treated with broccoli extract, tunicamycin, or a combination of the two (17 time points over 72 hours). Western blotting and qRT-PCR were used to assess ER stress markers, whilst the influence of broccoli on other cellular functions was analysed through appropriate assays. A qualitatively realistic mathematical model of part of the UPR was developed using nonlinear ordinary differential equations (ODEs), utilising experimental time series data for parameterisation and validation. The time series data identified novel expression profiles of proteins involved in the UPR, and highlighted that broccoli extract could significantly reduce the impact of tunicamycin on ER stress over time (p < 0.05), as well as reactive oxygen species (ROS) (p < 0.05) and mitochondrial dysfunction (p<0.05). These findings identify that broccoli extract appears to reduce the impact of tunicamycin on human adipocytes, and highlight the importance of modelling changes within the UPR to understand its response over time.
Supervisor: Not available Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology