CURRENT PROJECTS

Prof Sandosh Padmanabhan

 portrait of sandosh

COVID Knowledge Distiller

Lead: Prof Sandosh Padmanabhan

Funder: None

Website: https://www.kaggle.com/ravikiranbhaskar/covid-knowledge-distiller/ 

CoI's: Ravi Kiran Bhaskar (Washington Post), Tran Dennis Tran (University of Glasgow), Stefanie Lip (University of Glasgow), Linsay McCallum (Univeristy of Glasgow), Sandeep Reddy (Deakin University, Australia)

Summary: The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) late last year has not only led to the world-wide coronavirus disease 2019 (COVID-19) pandemic but also a deluge of biomedical literature. Traditional research models producing trustworthy and methodologically sound results takes time, which does not fit well in a pandemic where there is a desperate need for early actionable evidence. The ongoing coronavirus disease 2019 (COVID-19) pandemic has demonstrated the volume and velocity of scientific information that can be produced in a short period of time. Our international team is applying text mining and natural language processing methods on the COVID-19 Open Research Dataset (CORD-19), which is a resource of over 120,000 scholarly articles on COVID-19 and coronavirus related research. The CORD-19 dataset was made available for machine learning practitioners as an open-access database by a coalition including the White House, National Institutes of Health, and other partners but is now maintained by the Allen Institute for AI.

Dr Mark Danton

Portrait of Mark Danton

The influence of the COVID pandemic on the Scottish Congenital Heart Population

Lead: Dr. Mark Danton MD FRCS, Consultant Cardiac Surgeon, Royal Hospital for Children, Glasgow. Honorary Clinical Senior Lecturer (ICAMS).

Project Summary: 

This research seeks to determine the incidence and clinical consequence of SAR-CoV2 (COVID-19) in people with congenital heart disease (CHD) residing in Scotland. Patients with CHD encompass a heterogenous population with respect to age, underlying congenital cardiac abnormality and co-existing disease. They are potentially vulnerable to COVID-19 infection due to impaired cardiopulmonary anatomy and physiology.

All known patients in Scotland with CHD will be identified from paediatric and adult CHD registries. Data from the registries will be linked to national data-sets (prescribing, hospitalisations and deaths) and Public Health Scotland COVID datasets not only to determine the incidence and consequences of COVID infection in people with CHD but also the indirect effect of the pandemic on services and outcomes.

Seasonal outcomes will be compared to pre-COVID years and to the general population, matched for known COVID demographic risk factors, to determine if CHD confers an additional hazard and whether particular sub-groups within the CHD population are at greater risk.

Collaborators: Prof John Cleland Director of Robertson Centre for Biostatistics, University of Glasgow, Prof Alex McConnachie, Professor of Clinical Trial Biostatistics, Robertson Centre, University of Glasgow, Ms Sharon Kean Director, Information Systems, Robertson Centre. University of Glasgow, Dr. Niki Walker, Lead Consultant Adult Congenital Cardiologist Golden Jubilee National Hospital, Glasgow, Dr. Karen McLeod, Consultant Paediatric Cardiologist, Royal Hospital for Children Glasgow.

Dr Will Fuller

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Biochemical Characterisation of the SARS-COV2 Spike Protein

Lead: Dr Will Fuller

Summary: The COV2 Spike Protein facilitates docking and subsequent entry of virus particles into host cells. The Fuller Lab is investigating how this spike protein is synthesised, processed and modified in mammalian cells. We aim to identify essential steps in spike maturation and processing that could be targeted to reduce viral replication.

Collaborator: Professor Brian Willett, CVR

 

Dr Augusto Montezano

Augusto Montezano  Profile photo

ACE2 signalling and host responses to SARS-CoV-2 in vascular cells - implications in cardiovascular toxicities in COVID-19

Lead: Dr Augusto Montezano 

CoI's: Livia Camargo, Karla Neves, Francisco Rios, Rheure Lopes;

Funder: ISSF

Summary: This application is a collaborative effort between Early Careers from ICAMS, CVR and IMCSB. Our work will generate novel and timely understanding of how ACE2 and RAAS can influence the vascular outcomes of SARS-Cov-2 infection. Moreover, our findings will identify novel pathways that may be associated with cardiovascular complications itself independent of COVID-19 and expand the understanding of ACE2 signalling in cardiovascular cells.

Collaborations:  CVR – Vanessa Herder  IMCSB – Mario Rossi, Omar Janha, Gonzalo Tejeda.

Dr Francisco Rios

Portrait of Fran

Effects of Type I and Type III IFN on ACE2 and the immune response in vascular cells: implications in SARS-CoV-2 infection

Lead: Dr Francisco Rios

Co-i's: Augusto Montezano, Rheure Lopes 

Funder: ISSF

Summary: The aim of the project is to investigate the cardiovascular inflammation mediated by the SARS-CoV2 infection. This work may unravel mechanisms underlying endotheliitis and vascular damage in patients with COVID-19 and may also identify interferons (IFNs) as potential therapeutic targets.

Collaborations: CVR Elihu Aranday-Cortes 

Dr Ian Salt

Host Mitochondria dysfunction by viral hijacking as a key pathogenicity mechanism in COVID-19

Lead: Professor Kostas Tokatlidis (IMCSB)

CoI's: Dr Ian Salt (ICAMS)Prof Carl Goodyear (III), Dr Malcolm Watson (NHS/GGC), Dr Malcom Sim (NHS/GGC)

Funder: Wellcome Trust ISSF 

Project Summary: The exact mechanisms of pathogenicity underlying COVID-19 are still unknown, however, in severe cases, patients present with increased levels of lactate and profound hypoxia and multiple organ failure. Furthermore, recent studies have shown that SARS-Cov-2 does not induce an appropriate anti-viral/Interferon response. Notably, the ability to control hypoxia and cytokine/chemokine responses is heavily dependent on mitochondrial-driven metabolism. These observations suggest a dysregulated mitochondrial state. Importantly, several SARS-COV-2 viral proteins (e.g. Orf9b) interact with mitochondrial proteins (e.g. mitochondria antiviral signalling protein (MAVS), and have the potential to fundamentally affect mitochondria biogenesis, dynamics and oxidative metabolism. In support of this concept, viral proteins from several viruses (influenza and other corona viruses) are known to exert these deleterious effects. It is therefore essential that the impact of these viral protein-mitochondrial interactions are investigated, as they theoretically have the potential to drive key pathogenic mechanisms during infection. We aim to dissect this pathogenic mechanism by elucidating mitochondria dysfunctions using transfection of viral proteins in cell culture or primary patient cells (adipocytes and monocytes). We will evaluate mitochondrial defects in biogenesis, protein expression/assembly, dynamics, OXPHOS and ROS. In a second, parallel, approach we will use our expertise on isolated mitochondria and purified proteins to reconstitute the interactions between the viral and mitochondrial proteins to gain an in-depth understanding of the interactions. The elucidation of this pathogenic mechanism has the potential to lead to new therapeutic approaches targeting the translocation of the viral proteins to mitochondria and mitigation of the bioenergetic defects to redress the energy crisis of the host cells upon infection.

Dr Connor Blair

Connor in front of posterboard

Developing COVID19 inhibitor peptides of the ACE2 – Spike Protein complex

Lead: Dr Connor Blair (Baillie Lab)

Co-I's: Prof George Baillie 

Funder: ISSF

Summary: The ongoing COVID19 pandemic has led to ~11 million confirmed cases and >525,000 deaths globally since its outbreak (WHO COVID19 Sit-Rep: 04.07.2020). Many candidate therapies assessed in on-going clinical trials do not specifically target SARS-CoV-2, warranting the urgent and immediate development of novel and specific therapies. SARS-CoV-2 cell entry mechanisms rely heavily on the ability of its spike protein to bind with the host cell receptor ACE2. Key mutations (a result of adaptive evolution) within the receptor binding domain (RBD) of SARS-CoV-2 directly contribute to the higher ACE2 binding affinity (observed vs. SARS-CoV-1) and play a significant role in viral infection and subsequent pathogenic severity. Antibodies raised against SARS-CoV-2 RBD, as well as soluble ACE2 recombinant protein, have demonstrated a clear ability to block SARS-CoV-2 – ACE2 PPI and viral invasion across both SARS-CoV-1 and SARS-CoV-2 strains. However, recombinant antibody and protein-based therapies often pose higher immunogenic risk to patients, with poorer tissue penetration and higher production costs compared with shorter peptide analogues. Crystallographic studies have revealed crucial binding motifs between SARS-CoV-2 RBD – ACE2 that facilitate the protein-protein interaction (PPI), providing critical information that can be utilised in the rational design of selective, high affinity PPI disrupter peptide therapeutics. As this PPI interface spans a relatively large surface area (therefore not suitable for small molecules), targeted disruption with highly selective and potent ‘decoy’ peptides represent a promising antiviral/prophylactic therapeutic approach directed at blocking SARS-CoV-2 viral entry mechanisms.

Collaborations: Dr. Andrew Jamieson, Reader (School of Chemistry), Prof Andrew Tobin (IMCSB), Professor David Bhella (MRC CVR)