Elucidating the mechanobiological mechanisms underlying cardiomyocyte function using novel advanced imaging and force probing techniques

Project No: KTPS-NC-4
Intake: 2021 KTPS-NC

PROJECT OUTLINE

Almost all living cells in the body exert and experience the mechanics of their tissue micro-environment. New insights in the field of mechanobiology reveal that cell function is directly influenced by both the mechanical properties and mechanical forces of the surroundings. A pivotal event promoting the primary function of the human heart are robust and continuous contractile mechanical forces of cardiomyocytes to produce and sustain arterial blood pressure necessary to provide adequate perfusion of organs. However, following a heart attack (myocardial infarction), the heart muscle dies and is replaced by scar tissue. The scarred heart no longer pumps blood properly and about 40% of patients who develop heart failure die within 5 years, which is worse than most cancers. Every year over 200,000 people in the UK and 800,000 in the USA suffer heart attacks. The biomechanical events that cardiomyoctye face in the context of myocardial infarction, both following injury and subsequent recovery. Historically, advances in understanding the molecular biological mechanisms underlying key events in the myocardial infarction have been driven by innovations in biology, genetics, and molecular biology, yet could not provide answers about the poor recovery in strength and frequency of cardiac contractions. To address this challenge, we will establish a novel sensitive tissue-scale force probing functional assay at single cardiomyocyte and syncytial resolution to quantitatively study the relationship of the mechanical environment and cardiomyocyte injury and recovery. This research project aims thus to elucidate the mechanobiological mechanisms underlying cardiomyocyte injury and regeneration. We will make use of our previously well-established biological assays^1,2 and advanced high-throughput lighsheet imaging and sensitive force probing technologies^3,4. The project will rely exclusively on primary human cells or those derived from human stem cells^.

TRAINING OPPORTUNITIES

Well-established DPhil programme (NDORMS) with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
Cutting-edge novel advanced imaging techniques available in-house, including high-throughput lightsheet, super-resolution TIRF-SIM, and multi-dimensional FACS
Novel sensitive force probing technologies such as super-resolution Traction Force Microscopy
Emphasis on collaborative work using primary human tissues and cells or cells derived from human stem cells. Findings from these structures will be directly applicable to understanding normal human physiology and perturbations caused by disease
Highly collaborative environment with expertise ranging from microscopy to molecular biology and ex vivo models, as well as several other collaboration opportunities within the University of Oxford and worldwide

PUBLICATIONS

Lee G, Santo AIE, Zwingenberger A, Cai L, Vogl T, Feldmann M, Horwood NJ, Chan JK, and Nanchahal J, Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to Galert, PNAS, 2018.
Layton TB, Williams L, McCann F, Zhang M, Fritzsche M, Colin-York H, Cabrita M, Ng MTH, Feldmann M, Samson S, Furniss D, Xie W & Nanchahal J, Cellular census of human fibrosis defines functionally distinct stromal cell types and states, Nature Communications, 2020.
Colin-York H, Javanmardi Y, Barbieri L, Li Di, Korobchevskaya K, Guo Y, Hall C, Taylor A, Khuon S, Sheridan G, Chew TL, Li D, Moeendarbary E, and Fritzsche M, Spatiotemporally Super-resolved Volumetric Traction Force Microscopy, Nano Letters, 2019.
Colin-York H, Shrestha D, Felce JH, Waithe D, Moeendarbary E, Davis SJ, Eggeling C, and Fritzsche M, Super-resolved Traction Force Microscopy (STFM), Nano Letters, 2016.