About the Project
Fibrosis is a common endpoint of chronic inflammatory disease and is therefore implicated in >40% of deaths in the developed world. It arises as a response to unresolved injuries from a wide variety of sources. The Gooptu Group integrates structural, molecular, cell, and tissue biology approaches to define and target disease-relevant mechanisms of inflammation and fibrosis. The project will explore mechanisms of inflammation and fibrosis affecting two different organs - lung and liver. Specifically it will study the molecular processes whereby extracellular (TGF-beta1, mechanical stress, matrix stiffness, LPS) or intracellular (protein misfolding) pathological stimuli may result in inflammatory or fibrotic responses or cross-talk between the two. The mix of techniques used will depend on student preference and the most suitable approaches to the detailed aims defined prior to the start of the project. Methods used in the group to achieve such objectives cover a wide range of scales. Ex vivo tissue, primary cell, and cell model experiments include advanced fluorescence microscopy techniques (e.g. proximity ligation assay, super resolution microscopy). Biophysical, biochemical and high resolution structural and dynamic studies include SEC, CD, X-ray crystallography, NMR spectroscopy and (cryo-)electron microscopy) studies. We expect the protein structural and dynamic experiments will be greatly enhanced by incorporating modern in silico predictive approaches such as AlphaFold. Findings will be tested by knockout, knockdown and/or mutagenesis studies. The results will build understanding of molecular mechanisms of disease at high resolution and define novel therapeutic strategies.
Tissue and cell biology work is predominantly conducted within the Institute for Lung Health/NIHR Leicester BRC, whilst biochemical, biophysical and structural studies are conducted at the Leicester Institute of Structural & Chemical Biology (LISCB). These Institutes co-host the Gooptu Group. The project is expected to lead to a PhD in Biochemistry.
Potential candidates who have explored funding strategies to support their PhD research are encouraged to discuss further with Prof Gooptu ([Email Address Removed]).
References
The structural basis for Z α1-antitrypsin polymerisation in the liver. SA Faull*, ELK Elliston*, B Gooptu*, AM Jagger, I Aldobiyan, A Redzej, M Badaoui, N Heyer-Chauhan, ST Rashid, GM Reynolds, DH Adams, E Miranda, EV Orlova, JA Irving§, DA Lomas§ Science Advances, 2020 6:eabc1370
Deficiency mutations of α1-antitrypsin. Effects on folding, function and polymerisation. I Haq, JA Irving, AD Saleh, L Dron, JR Hurst, G Regan-Mochrie, N Motamedi-Shad, B Gooptu§, DA Lomas§. Am J Resp Cell Mol Biol, 2016, 54:71-80. doi: 10.1165/rcmb.2015-0154OC.
The molecular and cellular pathology of α₁-antitrypsin deficiency. B Gooptu, JA Dickens, DA Lomas. Trends in Molecular Medicine, 2014 20:116-127
Native ion mobility mass spectrometry, crystallographic and NMR spectroscopic characterisation of α1-antitrypsin conformational dynamics relevant to disease and therapy. MP Nyon, T Prentice, J Day, J Kirkpatrick, G Sivalingam, G Levy, I Haq, JA Irving, DA Lomas, J Christodoulou, B Gooptu§, Konstantinos Thalassinos§ . Protein Science, 2015, 24:1301-1312
Associations of latency with a1-antitrypsin polymerisation. L Tan, J Perez, M Mela, E Miranda, KA Burling, FN Rouhani, DL DeMeo, I Haq, JA Irving, A Ordóñez, JA Dickens, M Brantly, SJ Marciniak, GJM Alexander, B Gooptu§, DA Lomas§. International Journal of Biochemistry and Cell Biology, 2015 58:81-91
Structural dynamics associated with intermediate formation in an archetypal conformational disease. MP Nyon, L Segu, LD Cabrita, G Lévy, J Kirkpatrick, BD Roussel, AOM Patschull, R Kerr, UI Ekeowa, TE Barrett, N Kalsheker, M Hill, K Thalassinos, DA Lomas, J Christodoulou, B Gooptu. Structure 2012, 20:504-12
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