Current Research Projects
Students on the programme are working on the following projects:
Dissecting the role of Innate Lymphoid Cells in beneficial and pathological intestinal matrix remodeling
Researcher: Emma Hojmose Kromann, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Dr Joana F Neves
2nd Supervisor: Professor Eileen Gentleman
Project Description
While Inflammatory Bowel Disease (IBD) patients often present with abnormal extracellular matrix composition, defects in epithelial barrier and dysregulated intestinal innate lymphoid cell (ILC) populations, characterizing these complex interactions in multifactorial diseases has remained challenging. This project will dissect the cellular, molecular and mechanobiology nature of these interactions using our established co-culture system of ILC with human intestinal organoids. Using a multidisciplinary approach that includes flow cytometry, microscopy, molecular biology, microrheology, microindentation techniques and biomaterials methods we will monitor the impact of health and disease-associated ILC on the extracellular environment aiming to identify new therapeutic targets for IBD.
Star-Shaped: Investigating the mechanobiology and shape-function Dynamic of astrocytes using bioengineering, stem cells and optogenetics
Researcher: Ludovica Guetta, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Dr Andrea Serio
2nd Supervisor: Professor Simon Ameer-Beg
Project Description
This project aims to understand the relationship between cell shape, substrate stiffness and functional profile in human astrocytes. Astrocytes are responsible for many critical functions in the brain, and one key aspect of their biology is their complex and dynamic shape, which has recently been shown by our group and others as a main factor determining their functional profile and subtype. As cell shape is influenced by tissue mechanics, and evidence points to a role in mechanosensing for astrocytes in health and disease, we seek here to mechanistically dissect the interplay between substrate mechanics, shape and function in astrocytes.
Emergent cell-driven matrix mechanics
Researcher: Nandini Aggarwal, Randall Centre for Cell & Molecular Biophysics
1st Supervisor: Dr Susan Cox
2nd Supervisor: Professor Brian Stramer
Project Description
In fibrosis the extracellular matrix has been found to be remodelled to be more aligned. However, the feedback mechanisms which exist between the extracellular matrix and the fibroblasts which drive this process are poorly understood, as is the precise impact on the properties of the matrix. This project will use fluorescence microscopy, atomic force microscopy and modelling to understand how the fibroblasts can drive the creation of a more ordered matrix, and how the properties of the matrix in turn change the behaviour of the fibroblasts.
Image guided ultrasound and phase change nanodroplets to affect blood brain barrier and enhance efficacy of biotherapeutics in brain metastasis in breast cancer
Researcher: Owen James Harrison, Institute of Pharmaceutical Science
1st Supervisor: Professor Maya Thanou
2nd Supervisor: Dr Anthony Kong
Project Description
Breast cancer patients with brain metastasis have a poor prognosis, with the worse survival seen in triple negative breast cancer subtype. The blood–brain to tumour barrier (BBTB) is a morphological and physiological barrier that prevents the penetration of majority of large molecular drugs and nanoparticles as well as most small molecular drugs, preventing adequate delivery of anti-cancer drugs to brain metastases, which is a limiting factor in treating these patients. Here, we propose to develop a non-invasive focused ultrasound in combination with phase change nanodroplets to apply mechanical forces on the barrier to deliver anti-cancer drugs to brain metastases in preclinical models, which will have implication in translation of this technology for patients benefit.
Testing the role of atrial stiffness in fibrosis generation in the human atrium
Researcher: Tiffany Baptiste,
1st Supervisor: Professor Steven Niederer
2nd Supervisor: Professor Steven Williams
Project Description
Atrial fibrillation (AF) is a prevalent and progressive disease. Pathological atrial fibrosis is a major contributor to triggering and sustaining AF. Fibrosis is regulated by local tissue mechanics. Strain and stretch are known regulators of fibrosis, however, tissue stiffness is a regulator of fibrosis in other organs. The role of stiffness on atrial fibrosis is unknown. This project will investigate the role of stiffness in the development and progression of fibrosis in AF patients as a foundation for developing new and more effective therapies.
Mechanoregulation and cell-matrix interactions in human intestinal organoid-based models of Crohn’s disease
Researcher: Victor Diez Guardia, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Professor Eileen Gentleman
2nd Supervisor: Professor Abigail Tucker
Project Description
Therapeutic options to repair damage to the temporomandibular joint (TMJ) articulating surface are limited. Can emerging regenerative strategies that rely on approaches from mechanobiology, tissue engineering, and stem cell biology address this important clinical issue by promoting healing and helping to prevent the degenerative changes that result from trauma and disease? This project aims to engineer an osteochondral construct in vitro that can be used to repair damaged articulating surfaces of the TMJ. We aim to create a material that mimics the biological and mechanical characteristics of the mandibular condylar articular region, but also relies on cellular mechano-sensing to direct local osteogenic and chondrogenic differentiation of progenitor cells. Ultimately, such constructs could heal a defect in the mandibular condyle and prevent the degenerative processes associated with osteoarthritis in the TMJ.
Mechanochemical control of cancer cell genetic instability
Researcher: Leila Mouhib, Randall Centre for Cell & Molecular Biophysics
1st Supervisor: Professor Maddy Parsons
2nd Supervisor: Professor Tony Ng
Project Description
Tumours are complex, heterogeneous tissues involving many cell types supported by 3D extracellular matrix (ECM). Increased ECM stiffness is a hallmark of some cancers and is sensed by cells via receptor-mediated mechano-transduction pathways. The actin cytoskeleton plays a critical role in mechano-transduction by linking cellular compartments to receptors, leading to activation of a number of mechano-sensitive signalling pathways to regulate genetic instability, proliferation and invasion. However, the mechanisms controlling mechano- sensing triggers of DNA repair remain poorly understood. This project will use state-of-the-art imaging of mechanically-tuned 3D cancer models to determine the key molecular players in force- transmission DNA repair and their role in tumour progression.
Understanding the dynamic regulation of extracellular matrix structure and mechanics during embryogenesis
Researcher: Leonel Cardozo De Menezes E Souza, Randall Centre for Cell & Molecular Biophysics
1st Supervisor: Professor Brian Stramer
2nd Supervisor: Dr Susan Cox
Project Description
The extracellular matrix (ECM) is a polymer scaffold that is essential for tissue function. Its mechanical properties are dynamically controlled during normal physiology and disease, however it is unclear how its pliability is regulated. This dearth of knowledge is related to ECM complexity and the difficulty of analysing ECM structure and mechanics within living organisms. Here we will exploit our unique capacity to live image and genetically dissect ECM components and quantify ECM mechanical properties within developing Drosophila. This will allow us, for the first time, to understand how changes in ECM organisation and mechanical properties controls tissue structure and growth.
How do nanoneedles penetrate cells?
Researcher: Samuel McLennan, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Dr Ciro Chiappini
2nd Supervisor: Professor Mark Wallace
Project Description
Nanoneedle arrays hold significant promise as a minimally invasive method of drug delivery and sensing. Cells respond to the mechanical stimulus of nanoneedles by drastically remodeling their membrane, cytoskeleton and nucleus. Details of this interaction are starting to emerge, but to date we do not have a molecular understanding of precisely how membrane remodeling and permeability is regulated Here we will combine advanced nanofabrication techniques, with high-speed single-molecule tracking to map the membrane response to mechanical stimuli from nanoneedles.
Understanding the mechanical principles that regulate the final steps of cell division
Researcher: Ameh Ilu, Infectious Diseases
1st Supervisor: Dr Monica Agromayor
2nd Supervisor: Professor Sergi Garcia-Manyes
Project Description
It is well known that dividing cells experience dramatic changes in their cytoarchitecture as well as extensive membrane remodelling. In addition, a mechanical dimension is increasingly being recognised as a key factor influencing cell division. This is especially important in the contexts of tissue homeostasis and tumour progression. Using advanced imaging approaches and cell-based functional assays, this project aims at understanding the mechanisms linking mechanical cues from the adhesion signalling network to the cytoskeleton and membrane to provide the dynamic rearrangements needed during cytokinetic abscission, the last step of cell division.
Shaping the ear: exploring physical and mechanical cues
Researcher: Bowen Chen, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Professor Andrea Streit
2nd Supervisor: Professor Eileen Gentleman
Project Description
The ear is a complex sense organ whose normal function depends on its 3D-architecture. We know nothing about the mechanical forces that shape the ear, and how they are integrated with molecular cues. Our complementary expertise in ear biology, organoids and engineering is ideal to address this question. First, we will measure mechanical forces in vivo as the ear develops. Next, we will change the physical properties of the matrix surrounding ear organoids and investigate how this drives shape, cell and molecular changes. Engineering these next-generation organoids will allow us to investigate how complex organs are assembled across multiple scales.
The mechanobiology of ageing across scales
Researcher: Cristina Escalona Lopez, Physics
1st Supervisor: Professor Sergi Garcia-Manyes
2nd Supervisor: Professor Riki Eggert
Project Description
To activate force-induced transcriptional programmes, cells need to propagate mechanical stimuli from the extracellular matrix to the nucleus. However, recent evidences reveal that several mechanoensitive transcription factors fail to translocate to the nucleus upon mechanical stimulation in ageing cells, yet the molecular mechanisms remain largely unknown. Independent findings using single molecule nanomechanical experiments demonstrate that oxidative-stress related post-translational modifications on proteins physiologically exposed to force result in their loss of mechanical stability and ability to refold. This interdisciplinary PhD project combines single molecule and single cell mechanics, together with confocal/spinning disk microscopy and mass spectrometry, to unravel the mechanisms that underpin the loss-of-function of several proteins and lipid moieties involved in cellular mechanotransduction, with the overarching purpose to decipher and establish the first molecular connections between ageing and mechanotransduction.
Probing the mechanobiology of brain tumours with focused ultrasound
Researcher: Lauren Gomes, Surgical & Interventional Engineering
1st Supervisor: Dr Antonios Pouliopoulos
2nd Supervisor: Professor Jody Rosenblatt
Project Description
Brain tumours have a dismal prognosis with limited treatment options. As they progress, their mechanical properties change, indicating an influence of mechanotransductive cues on disease physiology. In this project, we will probe the mechanobiology of brain tumours using focused ultrasound (FUS). FUS provides a controllable source of acoustic radiation forces, which activates mechanosensitive ion channels, e.g., Piezo1. We will expose cancer cells to FUS in vitro and in vivo, and evaluate their response to variable mechanical stress. We will measure the activation of mechanical pathways and investigate potential treatment effects of repeated FUS exposures in a brain tumour mouse model.
Interfering with maladaptive mechanosignalling in cardiac fibrosis
Researcher: Lilianeleny Meoli, Comprehensive Cancer Centre
1st Supervisor: Professor Gilbert Fruhwirth
2nd Supervisor: Professor Elisabeth Ehler
Project Description
The limited regenerative capacity of the heart leads to replacement of contractile tissue by fibrosis, exerting mechanical stress on neighbouring cardiomyocytes. Our model system simulates cardiac fibrosis in vitro and induces alterations in cytoarchitecture and cellular function similar to cardiomyocytes in the diseased heart.
The aim of this project is to systematically quantify whether these adaptations to a fibrotic environment can be halted or even be reversed by exposing the cardiomyocytes to existing and new anti-fibrotic therapeutics that work for other cell types/disease settings.
The expected results will demonstrate whether this approach is effective to prevent maladaptive mechanosignalling in cardiomyocytes.
Understanding the mechano-regulation of ovarian ageing
Researcher: Milan Singh, Women & Children's Health
1st Supervisor: Dr Kim Jonas
2nd Supervisor: Professor Eileen Gentleman
Project Description
Ovarian ageing is a naturally occurring process resulting in declining fertility and ovarian senescence at menopause. The ovary ages chronologically faster than other organs, however the mechanisms controlling ovarian ageing remain elusive. There is increasing evidence that the extracellular matrix is dynamically modulated during ovarian ageing. This project aims to determine how ovarian stiffness changes across the reproductive lifespan of the ovary. We will use a combination of atomic force microscopy, mechano-modulation of ovarian follicle cultures, immunohistochemistry and qPCR to interrogate the aim. The outcome of which will provide key insights into the mechano-regulation of the ovary across its lifespan.
Mechano-metabolic tuning in the developing auditory system
Researcher: Yunzhe Guo, Centre for Craniofacial & Regenerative Biology
1st Supervisor: Dr Zoe Mann
2nd Supervisor: Professor Eileen Gentleman
Project Description
Mechanosensory hair cells (HCs) in the cochlear break down complex sounds into their component frequencies along the basal-to-apical long axis or the organ. Functional tonotopy relies on graded differences in the mechanical and morphological properties intrinsic to the cells, being specified during development. How a developing HC interprets signals within its local niche along the cochlea as a ‘tonotopic identity’ remains largely unknown. Using a novel approach, this project will address this question by investigating mechano-metabolic signalling in developing HCs. The project will investigate whether reciprocal feedback between metabolism and mechanics impacts specification of tonotopic identity in developing auditory HCs.