Prof Wei Li

Molecular basis of TGFß/BMP signalling in cardiovascular diseases

I am interested in how protein-protein recognition regulates TGFb family signalling, how defects in such interaction cause cardiovascular disease and how to employ such knowledge for therapeutic purposes.

There are over 30 TGFb family ligands in humans. Their signals are mediated by forming a signalling complex with one of the 7 type I receptors and one of the 5 type II receptors. These signalling complexes are further regulated by specific interactions with prodomain, co-receptors and ligand traps. The complexity of such protein-protein interaction network fine-tunes the outcome of TGFb family signalling, contributing to the homeostasis of many essential biological processes, such as vascular quiescence, wound healing and immune system.

The current focus of the group is on BMP9(10):ALK1:BMPRII pathways on vascular endothelial cells and their interactions with co-receptor endoglin (ENG). BMP9 and BMP10 form the major circulating BMP activity, signalling particular potently in vascular endothelial cells with EC50 in the pg/ml range. ALK1 is the type I receptor highly expressed on endothelial cells and specific for BMP9 and BMP10, whereas BMPRII is the ubiquitous type II receptor for over 15 BMP ligands.

Human genetics strongly support the importance of this pathway in cardiovascular diseases. Mutations in ALK1 and ENG cause Hereditary Haemorrhagic Telangiectasia (HHT), an autosomal dominant vascular disorder where patients have weak blood vessels in internal organs which can cause unexpected life-threatening bleeding. Mutations in BMPR2, GDF2 (encoding BMP9), BMP10, ALK1 and ENG have been found in patients with pulmonary arterial hypertension (PAH). These patients have elevated blood pressure in pulmonary circulation due to the remodelling of pulmonary arteries, eventually result in right ventricular hypertrophy and death due to heart failure. 

Our research on the molecular basis of endothelial BMP signalling pathways has led to a number of novel findings. We reported that BMP9 is regulated by redox-dependent proteolysis, prodomain does not confer latency to BMP10, soluble ENG does not inhibit but modifies BMP9 and 10 signalling in vascular endothelial cells, and the molecular recognition of these ALK1-ligands signalling in endothelial cells. We also show that loss of endogenous BMP9 leads to lung vascular leak in vivo, and have developed BMP9 variants that maintain endothelial protective function but lack the bone-forming activity. Such variants are currently under drug development programme at our spin-out company Morphogen-IX, which I am a co-founder with Prof. Nick Morrell and Dr Paul Upton.

We employ multidisciplinary approaches including protein chemistry, protein engineering, structural biology, biophysical and cell biology assays. We routinely use mammalian cell lines as well as control and patient-derived primary cells for signalling and functional assays. 

Group members:

Current:

Dr Jingxu (Jason) Guo

Dr Qiannan Wang

Dr Karolina Kostrzyńska

Dr Lu Long 

Miss Kate Quigley

Dr Xudong Yang

Past:

Dr Richard Salmon

Mr He Jiang

Mr Zhenquan Wei

Dr Aleksandra Lawera

Dr Zhen Tong

Dr Bin (Kevin) Liu

Dr Jennifer Wood

Dr Benjamin Constant

Collaborators:

Prof Antonio Vidal-Puig

Dr Mark Toshner

Prof Nick Morrell

Prof Helen Arthur - Institute of Genetic Medicine, Newcastle University

Professor Peter ten Dijke - Leiden University Medical Center