Characterisation of a newly identified, indispensible, transcriptional regulator of lymphangiogenesis (2016–2018)

Abstract:
The lymphatic vessel network is required for tissue fluid drainage and maintenance of fluid homeostasis. In both normal development and pathological conditions, lymphatic vessels form via lymphangiogenesis - the growth of lymphatic vessels from pre-existing vessels. This process is amenable to therapeutic intervention during metastasis because lymphatics support tumour spread. Recent evidence suggests that promoting lymphatic revascularisation will also be beneficial in cardiovascular disease. We use large scale, next-generation sequence driven, forward genetic screens in zebrafish to discover new genes that control lymphangiogenesis. By understanding the molecular control of this process, we can uncover the genetic aetiology of inherited vascular disorders and expand therapeutic avenues in lymphatic metastasis and cardiovascular disease. In recent years, we have characterized prominent new mechanisms in development published in high-impact journals. We have used a forward genetic screen to discover a role for the transcription factor MafB in embryonic lymphangiogenesis. MafB mutant zebrafish fail to form lymphatics but form a normal, functional blood vasculature. Preliminary data shows that MafB is enriched within angiogenic sprouts arising from embryonic veins. Using a transcriptome-wide approach, we identify candidate MafB-regulated genes for further investigation. This project grant will build on our substantial preliminary data. Our approaches include analysis of cellular phenotypes in novel zebrafish transgenic lines, whole embryo FACs, transcriptomics, bioinformatics and genome editing in zebrafish and mice. The outcomes of this project will have profound potential to build our understanding of vascular disorders, lymphatic diseases and to identify candidate genes for future therapeutic manipulation of lymphangiogenesis.
Grant type:
NHMRC Project Grant
Funded by:
National Health and Medical Research Council