Transcriptional pathways regulating lymphangiogenesis

Project Overview

The lymphatic vasculature network plays a crucial role in interstitial fluid homeostasis, lipid transport and immune surveillance. While the majority of lymphatic endothelial cells (LEC) share a venous endothelial cell (EC) origin, heterogeneity of gene expression has been seen in LECs within distinct lymphatic beds, and a minority of LECs have alternative lineages. While the crucial role of lymphangiogenesis during chronic inflammation and tumour metastasis is well established, recent data has also shown that increased lymphatic vasculature is also a hallmark of the post-MI heart. It is therefore crucial that we properly understand the source(s) of damage-induced lymphangiogenesis and the precise manner in which it is stimulated and controlled.

To study the regulatory frameworks controlling different types of vessel growth, my lab studies gene enhancers (cis-regulatory elements) active in different types of EC. Analysis of enhancers identifies the precise TFs required to achieve gene expression in discrete EC populations. Once these factors have been defined, transgenic animal models expressing reporter genes under the control of these enhancers become powerful tools in their own right. These animals can be used to study different transcriptional pathways at any stage of development or disease.

The aim of this studentship is to identify and characterize the regulatory pathways involved in lymphatic EC (LEC) differentiation. This will involve the identification and characterization of enhancers driving gene expression during LEC specification, the elucidation of the transcriptional regulators of these enhancers, and the role of these pathways during coronary lymphatic vessel formation and response to damage. This will involve both mouse and zebrafish transgenic models.

Training Opportunities

The project will provide training in a wide range of models, including transgenic mice and zebrafish, in silico enhancer prediction and cell culture. It is also likely that this project will include opportunities for genome-wide transcriptomic analysis. Our lab is part of the Burdon Cardiac Science Centre (within the Department for Physiology, Anatomy and Genetics) and affiliated with the Ludwig Institute for Cancer Research Oxford (LICR), where our primary lab will be located until an anticipated move to the new BHF Institute of Developmental and Regenerative Medicine on the same campus in 2021 when building is completed. Both DPAG and LICR provide support staff and core equipment, including confocal and time-lapse microscopes, and histology services.

Theme

Physiology, Cellular & Molecular Biology and Genetics & Genomics

Admissions

Project reference number: 1016

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Sarah De Val Oxford Ludwig Institute Oxford University, Old Road Campus Research Building GBR sarah.deval@ludwig.ox.ac.uk

There are no publications listed for this DPhil project.