Uncovering novel drivers of pathological collagen synthesis in the lung: the role of a SERPIN/LRP1 interaction in idiopathic pulmonary fibrosis (IPF)

Description

Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrosis in the lung, and manifests as shortness of breath, dry cough and loss of lung function. The 5-year survival rate is 46%¹. Fibrosis is a result of aberrant overproduction of collagen by lung fibroblasts. This project will break new ground in understanding the biology behind this process and seek new strategies for intervention.

The extracellular matrix (ECM)is a network of proteins which surround cells in tissues. The ECM exists in a tightly controlled, delicate balance between synthesis and degradation; a process which is disrupted in many diseases. Low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic receptor, essential for controlling the uptake of proteins from the ECM into the cell. SERPINs (serine proteinase inhibitors) are often described as ‘molecular mousetraps’ – covalent irreversible inhibitors, which control the activity of serine proteinases. SERPINs are well-described ligands of LRP1. We and others have previously shown they regulate the turnover of the ECM². SERPINE2 has been shown to be increased in fibroblasts of IPF patients³ and overexpression can drive fibrosis by increasing deposition of type-I collagen^4 5. Excitingly, we have demonstrated that transgenic mice deficient in fibroblast LRP1 are protected from fibrosis in a preclinical model of IPF, and recent evidence suggests LRP1-mediated endocytosis of SERPINE2 promotes fibrosis in the heart⁶.

In this project, we will investigate the role of a serpin/LRP1 interaction in driving collagen production in IPF. Using cell-based models, we will study the endocytosis of SERPINE2 in fibroblasts, and the effect of LRP1 binding on collagen production. Next, we will study the effect of a fibroblast-specific SERPINE2 knockout (KO) on fibrosis in a preclinical model of IPF and its similarity to our previously established LRP1 KO. Finally, we will develop a novel proof-of-concept peptide to disrupt binding of SERPINE2 to LRP1 as a pathway to anti-fibrotic therapy, and test this in our models.

The project will use a range of established and cutting-edge tools, including advanced protein methods, confocal microscopy, novel peptidomimetic characterisation, cell-based models, and transgenic mice in preclinical IPF models. The student will therefore gain broad research experience, making them well-placed for their future career.

The project is based in the labs of Dr David Wilkinson and Dr Kazu Yamamoto (Institute of Life Course and Medical Sciences (ILCaMS); University of Liverpool). Co-supervisors are Professor Geroge Bou-Gharios and Dr Sonya Craig (Aintree University Hospital). The Institute hosts a diverse research cohort, with 181 PhD students (55/45% female/male, 63/37% UK/overseas) in a state-of-the-art facility (William Henry Duncan Building, est. 2016). The student will join an exciting research environment, where they will be supported in their own ambitions and continued professional development. The project would suit an excellent candidate with a BSc (2:1 or above) or master’s degree in a biological/biomedical science, biochemistry or related discipline.

Application is via CV and cover letter to the Project Supervisor email (david.wilkinson@liverpool.ac.uk)