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(A*STAR) Investigating the role of Lrg1 in chronic kidney diseases


Project Description

Chronic Kidney Disease (CKD) affects 10-20% of adults and is a major and increasing public health burden. CKD has several aetiologies that share a final common pathway characterised by an inadequate angiogenic response to renal hypoxia that could potentially serve to enhance the fibrotic phenotype. Aberrant transforming growth factor-β (TGF-β) signalling is highly implicated in this response and the fibrotic phenotype. We recently identified a novel angiogenic factor, namely Leucine rich alpha-2-glycoprotein 1 (LRG1), and found that LRG1 promotes blood vessel formation through switching the endothelial transforming growth factor (TGF) β signalling towards the pro-agiogenic pathway. Whilst this angiogenic switch in TGFβ signalling has been known for many years, our work is the first to show that LRG1 is a major player in this phenomenon and explains in part the context dependency of TGFβ signalling. Given the multifunctional role of TGFβ at various stages during angiogenesis, it is likely that LRG1 is also involved in other TGFβ regulated processes. This poses an intriguing question regarding the role that LRG1 may play in CKD. This PhD project will investigate the role of Lrg1 during the pathogenesis of CKD using mouse models, Lrg1 knockout mice and also investigate the molecular mechanism using biochemical and cell biological assays.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. El Nahas, A. M. & Bello, A. K. Chronic kidney disease: the global challenge. Lancet 365, 331–340 (2005).
2. Levey, A. S. & Coresh, J. Chronic kidney disease. Lancet 379, 165–180 (2012).
3. Lan, H. Y. & Chung, A. C.-K. TGF-β/Smad signaling in kidney disease. Semin. Nephrol. 32, 236–43 (2012).
4. Wang, X. et al. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature 499, 306–11 (2013).
5. Glorieux, G. et al. New insights in molecular mechanisms involved in chronic kidney disease using high-resolution plasma proteome analysis. Nephrol. Dial. Transplant. gfv254 (2015). doi:10.1093/ndt/gfv254

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