centre for biomedical science research

Researcher: John George

The outer surface of gram-negative bacterial cells is made up of lipopolysaccharide (LPS). The synthesis of this essential molecule has to be tightly controlled and modulated in response to changing environmental conditions. Importantly, the LPS layer is known to protect the bacterial cell from physical or chemical attack, including antibiotic treatment. This study uses computational network analysis alongside traditional biochemistry to probe the regulatory mechanisms which operate during the synthesis of the bacterial cell envelope. Our work produced new insights into the ways that bacteria are able to synchronise the key elements involved in envelope biogenesis. Additionally, this work has highlighted potential antibiotic targets which could help in the fight against the antimicrobial resistance crisis.

Researcher(s): Dr Wayne Roberts

Platelet blood cells become activated in patients with atherosclerosis, resulting in platelet-microparticle (PMP) formation. PMPs are small membrane structures containing a range of bioactive molecules. The critical event driving heart attacks in patients with atherosclerosis is rupture of atherosclerotic plaques, causing clot formation in major blood vessels. PMPs have been proposed to contribute towards plaque rupture through inducing angiogenesis (forming leaky blood vessels through the plaque) however the underlying mechanisms were unknown. In this article we demonstrated that PMPs deliver the micro-RNA (small non-coding RNAs that control gene expression) Let-7a to endothelial cells (the cell type lining blood vessels) inducing angiogenesis. Through a range of molecular biology techniques, we demonstrated that Let-7a switched off the ability of endothelial cells to produce the anti-angiogenic protein thrombospondin-1 (THBS-1), resulting in angiogenesis. This study describes a new molecular mechanism by which PMPs induce tubule formation, opening up potential therapeutic avenues for treating cardiovascular disease.

Researcher(s): Professor Gary Jones

Hsp70 is a protein found in all living organisms. It carries out a variety of essential functions in cells including helping other proteins to fold into their correct functional three-dimensional structures. When proteins do not fold correctly this can result in a variety of human diseases such as Alzheimer’s, Parkinson’s, Prion diseases and cancer. This Scientific Reports article utilises a well-characterised yeast model to investigate the regulation of Hsp70 through a process called post-translational modification. It identifies key residues, that are conserved in human Hsp70 proteins, that are modified in vivo and modify Hsp70 function. This work identified new residue in this protein that undergo acetylation and provide a proof-of-principle that Hsp70 function can be manipulated through targeting of proteins that directly modify Hsp70, rather than targeting this essential protein directly. This opens up new potential avenues for Hsp70-targeted therapeutics. The importance of this work was highlighted by Faculty 1000 Prime.

Researcher(s): Dr Andrew Paterson, Dr Nat Milton, Dr Margarita Gomez Escalada

Formyl peptide receptors (FPRs) have a long-established signalling role in the immune system. They are also known to be present in the central nervous system where their role(s) are not yet fully understood. In this article published in PLoS One three cell lines of neural origin were studied to determine the impact of small molecule FPR ligands on neuronal differentiation and morphology. Novel differentiated morphological forms of the cells were identified following treatment with FPRa14, and actions via FPRs were confirmed using both pharmacological and siRNA knockdown interventions. This discovery will allow development of novel methods to produce cellular models of neurodegenerative diseases. The development of treatments for a range of neurological conditions including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, neurological cancers and neuropathic pain, as well as the field of neural regeneration could all benefit from the use of small molecule ligands to target neuronal FPRs.