Title: “Targeting endothelial BMP9 signalling for treating cardiopulmonary diseases”
Speaker: Dr. Wei Li, University of Cambridge.
Venue: Lecture Theatre 3, F Floor Medical School.
Time: 12:45pm – 1:45pm
Abstract: Endothelial dysfunction including heightened endothelial permeability plays an important role in many cardiopulmonary diseases, such as pulmonary arterial hypertension (PAH), sepsis and acute respiratory distress syndrome. Bone morphogenetic protein 9 (BMP9), a circulating vascular quiescence factor, signals on vascular endothelial cells (ECs) through activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPRII) and affords protection from endothelial apoptosis and permeability induced by inflammatory mediators. Importantly administration of recombinant BMP9 reverses PAH in multiple pre-clinical rodent models. A number of challenges remain for taking BMP9-based PAH therapy from bench to bedside, such as understanding the role of endogenous BMP9 on pulmonary vascular endothelium, and how endogenous BMP9 is regulated under physiological and pathological conditions, how to deal with the undesired bone-forming activity of BMP9. During this seminar, I will present unpublished data that endogenous BMP9 protects vascular endothelial integrity, the mechanism of which including that BMP9 regulates the expression of receptors essential for endothelial permeability. Circulating levels of BMP9 are reduced in endotoxaemic mice and sepsis patients, both of which are characterised by heightened endothelial permeability. Augmentation of BMP9 prevents the accumulation of interstitial oedema and neutrophils in the lungs of mice exposed to inhaled LPS. In addition, using structure-guided protein engineering, we have generated multiple non-osteogenic BMP9 variants, which are currently under further development in our Spin-out company Morphogen-IX. Our results greatly facilitate the translation of BMP9-based therapy from bench to bedside, also suggest that BMP9-based therapy may have therapeutic applications in other cardiopulmonary diseases that are caused by endothelial dysfunction.
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