Decoding the transcriptional program of vessel growth in health and disease (2016–2019)
Abstract:
Both blood and lymphatic vessels play critical roles during embryonic development and adult homeostasis. Abnormalities in embryonic vascular growth and development are associated with human disease including primary lymphoedema, vascular malformations associated with genetic disorders and solid cancer metastasis. To understand the molecular and cellular dysregulations that underpin vascular disorder, I will take advantage of an approach that combines developmental biology and preclinical model systems. I discovered the role of SOX18 as a transcriptional switch for embryonic and tumor-induced lymphangiogenesis. Further, I have found a conserved genetic interplay between SOX18 and VEGF-D pathways required for proper angiogenesis. I have developed a research program with a major aim to identify and characterize SOX¿dependent transcriptional mechanisms that instruct vessel formation during development and in pathological conditions. This research proposal revolves around the following themes: 1) To investigate SOX18/VEGF cross regulation in angio- and lymphangiogenesis. 2) To validate SOX18/VEGF axis in animal models of vascular diseases. 3) To characterise novel regulators of blood and lymphatic vascular development revealed by system biology resolution approaches. Biomedical significance: 1) This project will advance our knowledge of molecular driver involved in VEGF-driven vascular disease. 2) This research will open up avenues for combination therapies to manage pathological neo-angio-/lymphangiogenesis Biological significance: 1) This work will identify and characterise a SOX18 code of protein partners that drive endothelial cell fate. 2) This work will produce important new knowledge about how growth factors and transcription factors co-operate in feedback loops to modulate a developmental process such as vascular growth.
