Dr Wei Li
British Heart Foundation Senior Basic Science Research Fellow, Principal Research Associate
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Twitter: @wli225
LinkedIn: linkedin.com/in/wei-li-1b572044
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Biography
Dr Wei Li obtained her PhD degree from University of East Anglia in Biochemistry, focused on protein engineering and protein-protein recognition. She subsequently undertook postdoctoral research with Prof Jim Huntington at the Cambridge Institute for Medical Research, applying structural biology and protein crystallography to study thrombin inhibition by serine protease inhibitors (SERPINs) in the blood coagulation cascade. In 2010, she took up a British Heart Foundation Lectureship position at the Department of Medicine, University of Cambridge, and started working in the field of transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signalling. Alongside Prof Nick Morrell, she has been studying the extracellular regulation of BMP signalling in pulmonary arterial hypertension (PAH) and developed novel non-osteogenic variants of BMP9. She is a co-founder of Morphogen-IX, a Cambridge University spin-out company which was subsequently acquired by Centessa Pharmaceuticals. She was awarded British Heart Foundation (BHF) Senior Basic Science Research Fellow in 2020 to study the mechanism of endoglin function and its implication in hereditary haemorrhagic telangiectasia (HHT). In 2023, she was recognised as the BHF Research Fellow of the Year; also obtained Eureka International Certificate in Translational Medicine. She became a member of BHF project grant committee in May 2024.
Research Approach:
I am interested in how protein-protein recognition regulates extracellular TGF-beta and BMP signalling, how defects in such interaction cause cardiovascular diseases and how to employ such knowledge for therapeutic purposes. The current focus of the group is on BMP9(10):ALK1:BMPRII pathways in vascular endothelial cells and their interactions with co-receptor endoglin (ENG). BMP9 and BMP10 form the major circulating BMP activity, signalling potently in vascular endothelial cells with EC50 below 0.1 ng/ml. 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 life-threatening haemorrhage. 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 several novel findings. We reported that BMP9 is regulated by redox-dependent proteolysis, prodomain does not confer latency to BMP10, soluble ENG does not inhibit BMP9 and 10 signalling in vascular endothelial cells but does so in non-endothelial cells. We reported the first crystal structure of BMPRII in complex with a ligand in binary and ternary signalling complexes. 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. These variants are protected by a patent granted worldwide, and I became a co-founder of a university spin-out company Morphogen-IX.
We employ multidisciplinary approaches including but not limited to 1) protein engineering; 2) structural biology, 3) cell signalling and functional assays; 4) in vivo disease models; 5) Proteomic and RNAseq analyses. We routinely use mammalian cell lines to produce human proteins and use control and patient-derived primary cells for signalling and functional assays.
Current projects:
- Molecular basis of endoglin function in cardiovascular diseases, in particular, PAH, HHT and preeclampsia.
- Targeting the endothelial BMP signalling for the treatment of PAH.
- Therapeutic potential of BMP10 in a mouse model of HHT1.
Selected Publication
- Li W* & Morrell NW (2022) Endothelial Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension. Encyclopedia of Cell Biology, Second Edition. Volume 6, 2023, Pages 551-562. https://www.sciencedirect.com/science/article/pii/B9780128216187002467
- Guo J, Liu B, Thorikay M, Yu M, Li X, Tong Z, Salmon RM, Read RJ, ten Dijke P, Morrell NW & Li W* (2022) Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10. Nature Communications 13:2395
- Li W*, Lu L, Yang X, Tong Z, Southwood M, King R, Caruso P, Upton, PD, Yang P, Bocobo G, Nikolic I, Higuera A, Salmon RM, Jiang H, Lodge KM, Hoenderdos K, Baron RM, Yu PB, Condliffe AM, Summers C, Nourshargh S, Chilvers ER and Morrell NW* (2021) Circulating BMP9 protects the pulmonary endothelium during inflammation-induced lung injury in mice. Am J Respir Crit Care Med. 203:1419-1430.
- Salmon RM, Guo J, Wood JH, Tong Z, Lawera, A, Yu M, Beech JS, Grainger DJ, Reckless, J, Morrell NW and Li W* (2020) Molecular basis of ALK1-mediated signaling by BMP9/BMP10 and their prodomain bound forms. Nature Communications, 11, 1621.
- Lawera A, Tong Z, Thorikay M, Redgrave RE, Cai J, van Dinther M, Morrell NW, Afink GB, Charnock-Jones DS, Arthur HM, ten Dijke P and Li W* (2019) Role of Soluble Endoglin in BMP9 Signaling. Proc. Natl. Acad. Sci. USA 116: 17800-08.
Research collaborators
- Professor Antonio Vidal-Puig - HLRI
- Dr Mark Toshner -HLRI
- Dr Stefan Graf - HLRI
Full publications at PubMed
