ALR and redox regulation in Notch signalling-related human disease
The Notch signalling pathway is a highly conserved cell signalling system mediating cell-cell communication in a wide range of organism developmental processes. Notch receptors are single-pass trans-membrane receptors with a large extracellular domain that composed primarily of repeated small cysteine-rich EGF-like repeats. Redox pathways were found to mediate the Notch3 signalling in vascular smooth muscle cells (VSMCs), and functionally abnormal mitochondria were reported in the Notch3 mutant associated vascular diseases CADASIL. It is well-known that mitochondria play critical roles in all important biological processes, including response and adaptation to altered redox conditions. Recent studies have shown that biogenesis of the mitochondrial intermembrane space proteins is regulated by the redox-sensitive mitochondrial Mia40-Erv1/ALR system. Defect in this system has been linked to various human diseases, including cancer, Huntington’s diseases, familial amyotrophic lateral sclerosis, and several other neurological disorders directly or indirectly. ALR (Augmenter of Liver Regeneration, also called GFER) is a protein with multi forms/functions. Whilst a long form ALR (22 kDa) is located in mitochondrial intermembrane space acting as a sulfhydryl oxidase catalysing oxidative folding of Cys-rich proteins, a short form ALR (15 kDa) is found in the cytosol and extracellular with an unwell-defined function. The overall aim of this project is to understand how redox pathways regulate the Notch3 function. The potential interplay between ALR and Notch3 in VSMCs will be investigated. This project will also identify factors that are involved in oxidative folding and function of Notch3. The effects of ALR and newly identified factors on CADASIL mutant Notch3 will be studied. Cross-faculty collaboration (with Dr Tao Wang of FHMS) and multidisciplinary methods, including human genetic, cell biology, biochemical and biophysical methods, will be used. The results will provide insight in the molecular basis of protein redox regulation, Notch signalling, vascular diseases, and potential targets for future therapies.
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
Di Fonzo, A., D. Ronchi, et al. (2009). The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am J Hum Genet 84(5): 594-604.
Polimeno, L., B. Pesetti, et al. (2012). Decreased expression of the augmenter of liver regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells. Cell Death Dis 3: e289.
Wang, T., M. Baron, et al. (2008). An overview of Notch3 function in vascular smooth muscle cells. Prog Biophys Mol Biol 96(1-3): 499-509.
Yamamoto, Y., L. Craggs, et al. Review: molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathol Appl Neurobiol 37(1): 94-113.
Zhu, J. H., C. L. Chen, et al. (2011). Cyclic stretch stimulates vascular smooth muscle cell alignment by redox-dependent activation of Notch3. Am J Physiol Heart Circ Physiol 300(5): H1770-80.