Greening - Molecular proteomics, extracellular vesicles, intercellular signalling
Our laboratory is focused on understanding the molecular function of nano-sized biological extracellular vesicles and how their intercellular signalling is important in normal physiology and pathologies including cancer and cardiometabolic disease with the goal of identifying new deliverable therapeutic targets. The advanced-nano approaches developed in our lab have identified novel regulators of secretome (cell-derived secreted factors) and extracellular vesicle biology and have utilised this knowledge for commercial and translational potential. We use a multi-disciplinary approach to understand the molecular function of extracellular vesicles incorporating proteomics, cell biology, molecular biology, nanomaterials, nanobiotechnology, regenerative cell biology, physiology, and experts in molecular therapies with the goal of identifying new deliverable therapeutic targets and facilitate effective engineered nanoparticles for next generation cell-free therapies.
Understanding targeted delivery of biological extracellular vesicles
Extracellular vesicles (EVs) are secreted membrane-enclosed nano-sized particles (40–1000nm) important in intercellular communication to deliver biological information between cells. The molecular composition of these sub-cellular particles includes growth factor receptors, ligands adhesion proteins, mRNA, miRNAs, lncRNA and lipids that are derived from donor cells.
A number of studies have demonstrated that stem cell-derived EVs are the key mediator of tissue repair and regeneration. In addition, the composition of these particles is known to be altered in cancer and disease pathology suggesting them for useful in diagnostic and therapeutic purposes. Their endogenous origin and biological properties offer benefits over conventional drug delivery systems, such as liposome, synthetic nanoparticles and prompted the further application of EVs as delivery vehicles.
This project will investigate how to specifically load and deliver a biological payload in nano-carriers for the targeted and selective delivery to target organs/cells. Importantly, this will facilitate understanding the mechanisms of delivery and reprogramming target cells.
Developing new approaches for therapeutic extracellular vesicles
Extracellular vesicles (EVs) are a heterogeneous population of natural lipid bilayer-enclosed particles with direct relevance for intercellular communication. As native EVs, their endogenous properties facilitate their presence in the extracellular space, transverse biological barriers and deliver their biologically active molecular cargo to recipient cells/tissues to regulate cell function and phenotype. Moreover, EVs are an important component of the paracrine effect of stem/progenitor cell-based therapies, used as a drug delivery system in preclinical settings, and candidates as a standalone therapy.
Despite the heterogenous nature of native EVs, their endogenous properties make them natural delivery agents as well as features that can be improved using bio/engineering approaches to further their clinical potential for therapeutic application. EVs can be engineered to enhance/modify their stability, bioactivity, presentation and capacity for tropism and target binding at both cell type and tissue levels and modulate the intrinsic properties of native EVs and surface epitopes to improve their targeting efficiency in vivo.
This commercially focused project will address development of therapeutic strategies for cardiac protection and remodelling using cell-derived EVs. A focus on microfluidic EV generation, nanoparticle characterisation, state-of-the-art high-resolution mass spectrometry, post-translational modifications, and cardiac cell biology will lead to important developments in understanding EV generation, storage, and therapeutic application.
Understanding cardiac remodelling using human cardiac organoids
Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. To achieve this goal, a preclinical human model that mimics the complex and progressive nature of acute myocardial infarction is essential for detailed characterisation of human heart disease.
We aim to focus on extracellular vesicles called exosomes — key players of intercellular communication and heart physiology. Exosomes are nano-sized lipid-encapsulated vesicles that contain RNA and proteins which can mediate intercellular signalling to directly alter the function of target cells. We aim to use a novel human heart tissue model for disease modelling of HF and novel target discovery of therapeutic interest. A focus on state-of-the-art high-resolution mass spectrometry, phosphorylation signalling, integrated informatics, and cell biology will understand fundamental cardiac developmental and pathophysiological mechanisms in human cardiac homeostasis and disease.
Repairing a broken heart: exosomes in cardiac regeneration
Cardiovascular disease is a major cause of morbidity and mortality worldwide. Many cardiovascular diseases, such as heart failure and myocardial infarction, are associated with loss of functional cardiomyocytes (heart muscle cells). As results, people with cardiovascular disease have limited restricted physical activity, higher risk of stroke, decreased muscle fitness, which may impact choices in sport, employment, insurability and travel or driving. Since the heart has a limited regenerative capacity, it is not able to replace these cardiomyocytes on its own.
At the forefront of research, attempts to regenerate heart cells by injecting stem cells that can potentially repair a damaged tissue has gained significant traction. However, recent findings suggest that factors secreted by stem cells are themselves capable of regenerating damaged heart tissues, circumventing the need and ramifications of cell based therapies. A major player in this is a class of extracellular vesicles called exosomes. Exosomes are nano-sized lipid-encapsulated vesicles that contain RNA and proteins which can mediate intercellular signalling to directly alter the function of target cells.
We aim to explore novel approaches to regenerate the damaged heart (for example following myocardial ischemia) using exosomes derived from stem cells and potential design of exosome-based nanoparticles of therapeutic interest. A focus on state-of-the-art high-resolution mass spectrometry to understand fundamental cardiac developmental — and repair processes will promote the recapitulation of cardiac repair. Such therapies will directly improve life qualities by repairing the “broken heart”.
Meet the team
Dr Alin Rai
Qi Hui Poh
Adnan Shafiq (co-supervised with Professor Richard Simpson)