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(WIS) Determining the role of vascularisation in glomerular development


Project Description

The kidney has an essential role in filtering waste and toxins from the blood. When kidney function declines the impact on health is severe. In the UK, 1 in 10 people develop chronic kidney disease, which costs the NHS £3billion per year. Given this, new therapies are urgently needed in order to treat kidney disease.

The kidney is composed of hundreds of thousands of nephrons, the renal functional subunit. Each nephron contains a blood filter (glomerulus) and tubules, which reabsorb water and nutrients still required by the body and pass waste to the exterior. During the formation of the glomerulus, blood vessels invade into the primitive glomerular cells to form the filter. This process invokes a number of changes in both the blood and glomerular cells. What these changes are has not been fully characterised. Understanding better the molecular mechanisms involved in this period of glomerulogenesis is essential for us to comprehend why patients develop certain phenotypes in the blood filter due to genetic or environmental causes.

This project will use the zebrafish system to investigate the changes in gene expression that occur during invasion of the blood vasculature into the early glomerulus. The zebrafish contains a glomerulus that is highly conserved at the molecular and cellular level with the human blood filter. It’s transparency, amenability to genetic manipulation and high fecundity make it an ideal model system with which to understand glomerular development and disease. The PhD candidate will work with world-leading experts and will be fully supported in their training for the project, which has the following aims;

Aim1: Describe the vascularisation of the early zebrafish glomerulus – we will use transgenic zebrafish reporter lines to image, via live time-lapse imaging on a light sheet microscope, the invasion of the blood vasculature into primitive glomerular cells for the first time.

Aim2: Elucidate candidate genes involved in glomerular maturation in response to vascularisation – carried out in Israel, this component of the project will isolate glomerular and blood vessel cells that invade the glomerulus at varying stages of development of wild-type and tnnt2a deficient embryos. The depletion of tnnt2a will prevent the invasion of blood vessels into the glomerulus, permitting a comparison between vascularised and non-vascularised glomerular cell of the same age to be compared. These results will be obtained using the unbiased omics approach, RNA-seq.

Aim3: Functionally test the role of these candidates in zebrafish glomerulogenesis – candidate genes identified in the RNA-seq experiments will be knocked down in wild-type embryos by morpholino oligonucleotide and CRISPRi in order to test their functional significance to glomerular development and disease.

Successful outcomes from this exciting project will be the identification of novel players in kidney development and disease. This expansion in our knowledge of kidney disease has a high likelihood of identifying new therapeutic targets that will make a significant impact on the health of patients with kidney disease.

Entry Requirements
Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors honours degree or equivalent in a relevant subject area.

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 Weizmann Institute of Science, 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. Hen, G., Nicenboim, J., Mayseless, O., Asaf, L., Shin, M., Busolin, G., Hofi, R., Almog, G., Tiso, N., Lawson, N.D., Yaniv, K., 2015. Venous-derived angioblasts generate organ-specific vessels during zebrafish embryonic development. Development (Cambridge, England) 142, 4266-4278.
2. Chew, C., Lennon, R., 2018. Basement Membrane Defects in Genetic Kidney Diseases. Frontiers in pediatrics 6, 11.
3. Bantounas, I., Ranjzad, P., Tengku, F., Silajdzic, E., Forster, D., Asselin, M.C., Lewis, P., Lennon, R., Plagge, A., Wang, Q., Woolf, A.S., Kimber, S.J., 2018. Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors. Stem cell reports 10, 766-779.
4. Drummond, I.A., Davidson, A.J., 2010. Zebrafish kidney development. Methods in cell biology 100, 233-260.
5. Morello, R., Zhou, G., Dreyer, S.D., Harvey, S.J., Ninomiya, Y., Thorner, P.S., Miner, J.H., Cole, W., Winterpacht, A., Zabel, B., Oberg, K.C., Lee, B., 2001. Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nature genetics 27, 205-208.

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