“Diabetes mellitus and dysregulated angiogenesis in tuberculosis” is available for a PhD candidate who is motivated and has an excellent research track record.
Uncontrolled diabetes-TB patients are likely to die and remain infectious longer despite effective treatment. Angiogenic factors (AF) are upregulated in TB but the effect of clinically-approved angiogenic inhibitors on survival, and mycobacterial burden in diabetes-TB is unknown. We hypothesise that targeting dysregulated AF from uncontrolled diabetes reduces immunopathology in pulmonary TB.
The aims are to determine:
1. the expression of AF in diabetic-TB patients compared to TB patients without diabetes.
2. the regulation of AF in the diabetic-pulmonary TB murine model.
3. the effects of clinically-approved anti-AF drugs on immunopathology in the model
First, AF will be phenotyped in an existing cohort of diabetic-TB and TB patients. Proteins and gene expression will be analysed by Luminex bead array and single-cell RNA sequencing. Human lung granulomas will be examined for AF expression and 3D granuloma vasculature.
Next, AF expression on immune cells will be analysed by flow cytometry in the murine model. 3D granuloma vasculature/intracellular signaling pathways regulating angiogenesis will be examined.
Finally, angiogenesis inhibition on TB immunopathology will be examined. Diabetic-TB mice will be administered two angiogenic inhibitors with standard TB drugs. TB drug in murine lung, morphology of granuloma vasculature and hypoxia markers will be assessed.
This broad-based PhD project provides immunology training with key BSL3 experience. The results will positively impact the launch of a clinical trial on diabetic-TB patients.