Defining the molecular structure-function relationships of extracellular vesicles from dying cells.

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Apoptosis removes unwanted cells in the body. During this process, apoptotic cell-derived extracellular vesicles (acdEV) are released but the full function and structure of acdEV have never been defined. We have shown that acdEV recruit phagocytes and exert anti-inflammatory effects to promote safe, controlled and efficient removal of dying cells. This is important as it ensures successful apoptotic cell clearance and avoidance of inflammation and autoimmunity.

Our previous work highlights important questions in the field of cell death that will be answered in this project. What is the molecular composition of the acdEV? How does this composition relate to acdEV function in ensuring efficient removal of apoptotic cells? This work programme will define those key molecular components that mediate the beneficial immune-modulatory functions of acdEV.

We will identify acdEV (1) PROTEIN components and, using surface biotinylation, acdEV surface proteins - proteins that may mediate the interaction of acdEV with cells of the immune system; (2) LIPID MEDIATORS that may modulate inflammation. Such mediators have been shown to promote resolution of inflammation. Here we will look at the lipidome of acdEV for the first time; and (3) MICRORNA content. We will assess the miRNA ability to mediate intercellular communication and exert anti-inflammatory effects through gene silencing. Using over- or under-expression systems and the use of specific inhibitors we will confirm the role of individual molecular players in the ability of the acdEV to interact with the immune system through in vitro and in vivo functional studies.

This unique work will generate the first comprehensive structure-function analysis of acdEV. It will define those components that interact with the immune system to promote apoptotic cell removal and resolution of inflammation. Thus this work will provide essential detail to enable the manipulation of apoptotic cell clearance for therapy.

Intercellular communication underlies effective functioning of multicellular organisms and extracellular vesicles (EV) are novel mediators of this communication. EV are known to impact on a number of physiological and pathological processes. Our work will focus a particular class of EV (apoptotic cell-derived EV; acdEV) that have never been studied in a detailed and comprehensive manner. This work is of great importance as cell death is vital to healthy ageing and the manner in which cell corpses interact with the immune system is fundamental to the control of inflammation, immune responses and the prevention of important age-associated pathologies (e.g. cardiovascular disease, cancer, inflammation and autoimmunity). The fundamental research outlined in this proposal is thus directly relevant to the BBSRC strategy of Bioscience for Health. Through a better understanding of the mechanisms by which dying cells interact with and modulate the immune system, we will seek to manipulate these normal physiological processes for therapeutic gain.
WHO WILL BENEFIT? This work is of very broad appeal. In the short-term, beneficiaries will be academic e.g. basic scientists and clinicians in a wide range of research and therapeutic areas (e.g. cell death, immunology, inflammation, cardiovascular disease, EV and cellular communication). These will naturally include the immediate workers on this project and other local research groups and students. Our work will significantly advance the field through improved fundamental detail of cellular communication and control of inflammation. Consequently this research will enhance our basic understanding of both physiological and pathological processes in a wide range of disease. For example, EV are of particular interest to the field of cardiovascular disease. By defining the fundamental communication factors released from dying cells we will shed new light on this important pathology where recruitment of monocytes to dying cells in the atherosclerotic plaque drives disease.
In the longer term, beneficiaries will include parties interested in detailed mechanisms for control of inflammation and cell communication (e.g. Pharmaceutical companies, clinicians and patients suffering inflammatory diseases). Ultimately, this work (through its relevance to ageing) will also be of interest to the general public.
HOW WILL THEY BENEFIT? This work will highlight mechanisms by which apoptotic cells interact with the immune system - fundamental for control of inflammation. It will detail molecular mechanisms that recruit phagocytes to identify and silently remove unwanted cells, by defining 'find me' signals and immune-modulatory signals. Such improved knowledge of mechanisms that recruit phagocytes to sites of cell death will provide valuable innovative approaches for modulating inappropriate phagocyte recruitment to sites of cell death. Such sites include tumours and atherosclerotic plaques. In these cases macrophages infiltrate yet fail to resolve the pathological lesion. Consequently the ability to inhibit phagocyte recruitment may be of therapeutic benefit. Furthermore defining new anti-inflammatory factors within acdEV will allow production of synthetic EV to be tested for efficiency as therapeutics.
The assembled team has all the skills for the fundamental studies and the production of novel potential therapeutics. Human therapy is a key long-term goal. Therefore, in the nearer term, output from this research will lever additional funding for focus on development of innovative therapies that may be developed in house at Aston through the marriage of the basic science (Devitt, Griffiths) and the liposome research team (Prof Perrie) within Aston Pharmacy School. The assembled world-leading team of investigators and collaborators will drive the translation of our cutting edge, basic bioscience.