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Exploring the contribution of lymphatics towards diabetic kidney disease and their potential as a therapeutic target
Supervisors: Dr David Long, Professor Luigi Gnudi (King’s College London)
Project Description:
This PhD studentship aims to determine how lymphatics contribute to diabetic kidney disease (DKD) and whether they can be exploited as a therapeutic target to alleviate disease progression. It is emerging that lymphatics are capable of actively modulating the inflammatory environment in diseased organs. These vessels therefore represent a promising therapeutic target for several diseases, which our group and others have demonstrated to be the case for cystic kidney disease, ischaemic cardiac failure and obesity. In DKD, the most common cause of renal failure worldwide, it is known that lymphatics in the kidney expand and this may be related to scarring of the kidney and decline in renal function. However, the exact role of lymphatics in DKD, and whether they can be targeted to halt or reverse the consequences of diabetes on the kidney, are unknown.
This studentship will begin by exploring the role of kidney lymphatics in DKD. To do this, the student will utilise a new mouse model of DKD that we have developed in our laboratory. The student will use innovative three-dimensional (3D) microscopy techniques and a novel quantitative analysis framework to distinguish structural changes to kidney lymphatics over the course of DKD. The student will then perform single cell RNA sequencing (scRNA-seq); capable of reading thousands of genes from each cell, to probe the effect of DKD on the lymphatic endothelial cell transcriptome, and how lymphatics might interact with other cell types within the diabetic milieu to promote or suppress renal inflammation and fibrosis in diabetes. Finally, the student will attempt to exploit kidney lymphatics as a therapeutic target for DKD using gene therapy to deliver vascular endothelial growth factor (VEGF)-C; promoting lymphatic vessel growth, to the diabetic kidney.
Collectively, this PhD studentship will generate insights into the role of lymphatics in DKD and validate whether kidney lymphatics can be targeted to prevent or reverse decline of renal function. Furthermore, this project provides a unique opportunity for the PhD student to learn and apply a range of novel techniques to understand the biology of a complication affecting a significant proportion of patients with diabetes.
References
1. Jafree et al J Am Soc Nephrol. 2020 Apr 15. doi: 10.1681/ASN.2019121320. (Epub ahead of print).
2. Jafree et al Elife. 2019 8. doi: 10.7554/eLife.48183.
3. Huang JL et al J Am Soc Nephrol 27: 69-77, 2016.
4: Hernandez-Diaz I et al Diabetes 2019 68:1841-1852.
5: Gnudi L, et al. Trends Endocrinol Metab. 2016 27: 820-830.