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Dr Natasha Harvey

University of South Australia

NHarvey


Presentation Title

 

Defining the genetic and developmental basis of human lymphatic vascular disease

 Cell and Developmental Biology Session

 

Abstract 

Lymphatic vessels are an integral component of the cardiovascular system. These specialised vessels play key roles in fluid homeostasis, dietary lipid absorption and the regulation of immune cell trafficking. We and others recently demonstrated that heterozygous germline mutations in the zinc finger transcription factor GATA2 underlie Emberger syndrome, a disorder characterised by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (Kazenwadel et al., Blood, 2012, Ostergaard et al., Nat Gen, 2011). This discovery was the first to demonstrate an important role for GATA2 in the lymphatic vasculature. We subsequently determined that Gata2 is crucial for lymphatic vascular development by orchestrating the construction and maintenance of lymphovenous and lymphatic vessel valves (Kazenwadel et al., J Clin Invest, 2015). Our current work aims to define the mechanisms by which GATA2 controls valve morphogenesis in the lymphatic vasculature. We have identified a novel GATA2-bound enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that has the capacity to drive reporter gene expression to the lymphatic vasculature and in particular, at high levels in valve endothelial cells. Current work aims to investigate the requirement of this enhancer for lymphatic vessel valve development, together with the mechanisms that regulate enhancer activity. We have also identified additional key target genes of GATA2 in the lymphatic vasculature, at least two of which are also mutated in human lymphoedema syndromes. These genes and their roles in lymphatic vessel morphogenesis will also be discussed. Ultimately, understanding the genetic basis of lymphoedema will inform our knowledge of the cellular events and signalling pathways important for building functional lymphatic vessels, information that will underpin the design of novel, targeted therapeutics able to promote lymphatic vessel function and thereby treat lymphoedema.

 

 

 

Last Updated on Friday, 06 October 2017 07:07
 
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