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Primary Supervisor:
Professor David Long and Dr Daniyal Jafree
Project Description:
Background
Lymphatic vessels are traditionally considered as a route for the clearance of tissue fluid, small molecules and immune cells (1). More recently, a new way has been identified in which lymphatic vessels participate in development and disease, through the secretion of molecular ‘signals’ that modulate the surrounding microenvironment. Molecules derived from lymphatics facilitate regeneration of stem cell niches in the heart (2), skin (3) and intestine (4), with implications for diseases affecting these organs. Identifying the molecules that lymphatic secrete and how these affect the microenvironment around them therefore may provide therapeutic targets for diseases with limited treatments.
Our group is interested in lymphatic vessels within the kidney. This is based on a major clinical need: the kidneys are vital for filtering blood and maintaining bodily fluid homeostasis, acid base balance and beyond. Chronic kidney disease is initiated by either genetic or acquired causes and affects over 800 million individuals worldwide with limited treatment options. The kidney contains a network of lymphatic vessels that invades the organ during its development (5). However, the role of lymphatics for the growth and functioning of the kidney remains elusive. We hypothesise that, like other organs, kidney lymphatics secrete signals to surrounding cells which regulate fundamental processes such as the growth, differentiation and renewal of kidney stem cells in health and disease.
Aims and Objectives (with timeline)
The aim of this PhD project is to elucidate the role of lymphatics during development and regeneration of the kidney. To do this, the PhD student will perform a range of techniques to manipulate lymphatics and molecules which they secrete:
(i) Performed timed “deletion” of lymphatics in the kidneys of mice and examine the effect upon the kidney including the maturation and phenotype of specialised kidney cells and function of the organ (0-18 months)
(ii) Co-culture human kidney organoids with lymphatic cells and examine the effect upon organoid growth and differentiation and the molecules responsible using single-cell transcriptomics (18-24 months)
(iii) Harness gene therapy technologies and a novel delivery system using ultrasound to administer lymphatic-derived molecules to treat a mouse model of polycystic kidney disease: the most common genetic cause of kidney failure (24-36 months)
Methodology
There will be an opportunity to learn fundamental techniques such as animal husbandry, molecular biology and histology, and cutting-edge methods including high-resolution three-dimensional imaging using confocal and lightsheet microscopy systems, the generation of hybrid lymphatic-kidney organoids, gene therapy, ultrasound delivery systems and single-cell transcriptomics.
References
1. Jafree & Long. J Am Soc Nephrol. 2020. 31:1178–90.
2. Liu et al. Nature. 2020. 588:705–11.
3. Gur-Cohen et al. Science. 2019. 366:1218–25.
4. Niec et al. Cell Stem Cell. 2022. 29:1067–1082.
5. Jafree et al. Elife. 2019. 8:48183.
Contact Information:
Professor David Long