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  • Project No: #OxKEN-2022/19
  • Intake: OxKEN 2022

PROJECT OVERVIEW

Heart disease is the leading cause of morbidity and mortality in the West. Every year 205,000 people in the UK and 805,000 people in the US suffer a myocardial infarction. For patients who survive the initial event, the damaged cardiac muscle is replaced by fibrous tissue. Forty percent of these patients eventually develop heart failure, which affects 38 million people worldwide, with the current 6.6 million in USA projected to increase to >8 million by 2030. Despite healthcare expenditure for heart failure in the USA exceeding $30Bn per year and expected to increase to $70Bn by 2030, 5 year survival is only ~60%, worse than most cancers. Current treatments are aimed at limiting ventricular dysfunction and there is no approved therapy for promoting myocardial regeneration, reducing fibrosis and leading to sustained improvement in cardiac function (Cahill et al., 2017).

We have previously shown that exogenous administration of fully-reduced HMGB1 (FR-HMGB1) promotes regeneration of bone, skeletal muscle and blood following injury, where it acts on resident stem and progenitor cells to transition them to GAlert (Lee et al., 2018). We have recently shown that intravenous administration of FR-HMGB1  at the time of myocardical infarction in mouse model leads to 40% improvement in left ventricular function. Others have shown in a large animal model that local injection of HMGB1 leads to improved cardiac function, in part by promoting cardiomyocyte survival and angiogenesis (Bauza et al., 2019). We have also shown that the heart contains a population of progenitor cells (Smart et al., 2011) and demonstrated the crucial role of immmune cells following acute myocardial infarction (Klotz et al., 2015). 

This project will profile the dynamic cellular landscape of heart regeneration following myocardial infarction. Using established murine models and advanced sequencing techniques, including single cell and bulk RNA-sequencing, we will define how FR-HMGB1 orchestrates myocardial regeneration to identify central regulators of cardiomyocyte repair and homeostasis, including intracellular signalling pathways. Our expertise in computational biology and cardiovascular medicine will support the construction of a single cell atlas of heart repair and uncover key cell types and states that govern this process. A range of functional assays developed in our group will support validation of cell subsets identified in addition to a novel multiplex imaging platform enabling cellular biomarkers to be spatially mapped in vivo. In addition, this project will define the intracellular signalling pathways activated by FR-HMGB1.

 KEYWORDS

Cardiac regeneration, myocardial infarction, single cell RNA-sequencing, HMGB1 signalling

TRAINING OPPORTUNITIES

The successful candidate will benefit from supervision by a surgeon scientist with a focus on translational medicine, two renowned authorities on the cardiac regeneration and a clinical cardiologist. In addition, you will be supported by two junior supervisors with expertise in HMGB1 biology and computational biology. 

You will be based in the modern building and laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation. The project will use a combination of human samples and murine models of myocardial infarction. There is support available from post-doctoral scientists and lab managers in our groups. This project will benefit from:

  • Cutting-edge cardiac biology and computational biology techniques available in-house, including tissue culture, flow cytometry and cell sorting, myocardial infarction models, MRI and next generation sequencing including single cell RNA-sequencing analysis
  • Emphasis on translational work: murine cardiac models optimised for therapeutic development and integration in a team working on translational research spanning from bench to bedside 
  • Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists 
  • Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo models and computational biology / genomics analysis. You will also have the opportunity to participate in several other collaboration within the University of Oxford and worldwide.

KEY PUBLICATIONS

  1. Bauza, M.D.R., C.S. Gimenez, P. Locatelli, A. De Lorenzi, A. Hnatiuk, M.C. Capogrossi, A. Crottogini, L. Cuniberti, and F.D. Olea. 2019. High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction. Drug Deliv Transl Res 9:935-944. doi: 10.1007/s13346-019-00628-z.
  2. Cahill, T.J., R.P. Choudhury, and P.R. Riley. 2017. Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat Rev Drug Discov 16:699-717. doi: 10.1038/nrd.2017.106.
  3. Klotz, L., S. Norman, J.M. Vieira, M. Masters, M. Rohling, K.N. Dube, S. Bollini, F. Matsuzaki, C.A. Carr, and P.R. Riley. 2015. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522:62-67. doi: 10.1038/nature14483.
  4. Lee, G., A.I. Espirito Santo, S. Zwingenberger, L. Cai, T. Vogl, M. Feldmann, N.J. Horwood, J.K. Chan, and J. Nanchahal. 2018. Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Proc Natl Acad Sci U S A 115:E4463-E4472. doi: 10.1073/pnas.1802893115.
  5. Smart, N., S. Bollini, K.N. Dube, J.M. Vieira, B. Zhou, S. Davidson, D. Yellon, J. Riegler, A.N. Price, M.F. Lythgoe, W.T. Pu, and P.R. Riley. 2011. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474:640-644. doi: 10.1038/nature10188.

 CONTACT INFORMATION OF ALL SUPERVISORS

jagdeep.nanchahal@kennedy.ox.ac.uk

paul.riley@dpag.ox.ac.uk

robin.choudhury@cardiov.ox.ac.uk

ana.espiritosanto@kennedy.ox.ac.uk

thomas.layton@kennedy.ox.ac.uk