About the Project
Obesity drives chronic inflammation and immune activation. This results in dysregulated metabolism, insulin resistance linked to diabetes, cardiovascular disease and cancer. Adipose tissue contains immune cells, in particular macrophages. Under lean conditions, adipose tissue and macrophages are anti-inflammatory and maintain homeostasis. While in obesity adipose becomes pro-inflammatory, upregulating inflammatory macrophages. Secreted hormones and cytokines provide intercellular communication between fat-storing adipocytes and macrophages. Interestingly, accumulation of fat at different storage depots is more or less associated with metabolic disease: visceral (abdominal) fat depots are associated with lipid imbalance and metabolic syndrome (diabetes); whereas subcutaneous depots (hips, thighs, gluteal) are protective with respect to lipid balance and mitigation of metabolic disorders. https://www.diabetes.co.uk/body/visceral-fat.html, https://www.karger.com/Article/FullText/485183
We lead an EU PhD training network to study the role of Tribbles in metabolism, immunity and cancer http://train-itn.eu/ ; within this we are investigating how pseudokinase Tribbles-3 (TRIB3) functions at the interface of metabolism and inflammation. Our group have found that mice lacking TRIB3 gain more weight and show altered depot dependent fat storage with altered adipocyte numbers and immune cell function. Recent work from our consortium showed TRIB3 may play a role in transcriptional regulation. Identification of transcriptional targets of TRIB3 in adipocytes and immune cells from different fat depots will reveal mechanisms and pathways regulating lipid storage, metabolism and how this may be imbalanced in disease.
1. TRIB3 regulates adipocyte function by activating specific adipose-depot-dependent gene targets.
2. TRIB3 is critical in the cross-talk between immune cells and adipocytes underlying phenotypic differences observed in depot-dependent adipocity.
In this PhD project you will use CHIP-seq and RNA-seq data recently produced by our group for bioinformatics analysis to identify TRIB3-specific transcriptional regulation in adipocytes and adipose tissue immune cells (supported by University of Sheffield bioinformatics group). Expression differences for TRIB3 transcriptional targets will be validated in wildtype and TRIB3-/- adipose tissues (already collected) and in isolated adipocytes and adipose-tissue immune cells.
Human adipocyte-macrophage co-culture ± TRIB3 expression (by siRNA knockdown) will be performed to assess regulation of adipocyte proliferation, fat accumulation and cytokine secretion.
Outcomes: how TRIB3 influences cross-talk between adipocytes and immune cells will identify mechanisms regulating depot-dependent fat storage.
Interested candidates should in the first instance contact Dr Heather Wilson, email@example.com
How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Please clearly state the prospective main supervisor in the respective box and select “Infection, Immunity and Cardiovascular Disease” as the department.