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Linking genetics to drug discovery for cardiovascular disease

James Black Centre, London

Title: Linking genetics to drug discovery for cardiovascular disease

Abstract

The seminar will focus on our studies in cardiovascular genomics, cell biology, and drug discovery. In the area of computational biology, we have developed unsupervised approaches to study genetic mechanisms of disease. By comparing histone modification data across hundreds of diverse cell-types, we identified exceedingly rare domains of the human genome (comprising only 1.4% of bases) that are safeguarded by conserved regions of facultative heterochromatin, which we term domains under “cellular constraint”. Similar to evolutionary constraint scores, we calculate cellular constraint scores (CCS) for every base in the human genome. When analysing orthogonal genetic data, CCS values function as a genome-wide weighting metric to quantify the probability that any genetic feature plays a key role governing cell decisions and functions. Not only can CCS values reveal genetic causes of disease, our data provide compelling evidence that CCS values can identify drug targets with higher likelihood of approval by the FDA and improves accuracy and versatility of machine learning pipelines to predict patient outcomes.

In the context of drug discovery, we have discovered a new therapeutic strategy to treat myocardial infarction (MI). This work stems from our elucidation of ASIC1a as a novel target for ischemic injuries and our discovery of Hi1a, the most potent known pharmacological inhibitor of this channel, from the venom of an Australian funnel-web spider. In preclinical studies we showed that Hi1a is a safe and potent therapeutic candidate that reduces brain injury after stroke, improves heart recovery after myocardial infarction (MI), and enhances the performance of donor hearts procured for transplantation. These remarkable therapeutic properties stem from Hi1a’s ability to protect cells from ischemic injury by inhibiting ASIC1a

Speaker: Dr Nathan Palpant 

Biography:

Associate Professor Nathan Palpant received PhD training at the University of Michigan and postdoctoral training at the University of Washington’s Institute for Stem Cell and Regenerative Medicine. In 2015 he established his independent research group at the University of Queensland’s Institute for Molecular Bioscience. Dr Palpant is a Heart Foundation Fellow and recipient of the International Society for Heart Research Young Investigator Award and the Lorne Genome Millennium Science Award. His research program focuses on mechanisms of cardiovascular development disease and involves interdisciplinary approaches in stem cell biology, genetics and genomics, and drug discovery. Dr Palpant is co-founder of Infensa Bioscience, which aims to develop new therapeutics for ischemic heart disease

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