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Apoptotic cell clearance: From basic biology to new therapeutic strategies for chronic respiratory disease.

Project Member(s): Gillis, C.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC CJ Martin Fellowships)
National Health & Medical Research Council (NHMRC CJ Martin Fellowships)

Start year: 2020

Summary: Old, damaged or used cells normally die in a regulated fashion by apoptosis, and their corpses are removed by professional and non-professional phagocytes, in a process termed efferocytosis. Efficient clearance of dying cells is critical for the maintenance of healthy tissues and for proper inflammation resolution. Defective efferocytosis contributes to numerous autoimmune and inflammatory diseases, perpetuating inflammation and obstructing organ function. Inflammatory lung pathologies, such as chronic obstructive pulmonary disease (COPD) and asthma, are amongst the most important public health burdens in Australia and worldwide. Current therapies for these conditions have poor efficacy to inhibit chronic inflammation and prevent progressive damage. Moreover, airway damage and inflammation are associated with an excess of dead and dying cells. We hypothesise that apoptotic cell clearance can be boosted by small molecules that target the engulfment machinery, and that this could be an effective avenue for therapeutic development. In the Ravichandran host lab (VIB Ghent), I will perform an unbiased drug screen to identify small molecule candidates that can enhance apoptotic cell uptake – that is, a ‘gain of function’ screen for efferocytosis. We will address the immune consequences of pharmacologically enhanced engulfment on professional and non-professional phagocytes, and employ state-of-the-art biomolecular, nucleomics and proteomics approaches to define the cellular targets of these candidate molecules. We anticipate that these findings will provide insight into molecular pathways of apoptotic cell uptake and processing. In the Hansbro lab (HMRI Newcastle) I will apply these findings to study apoptotic cell clearance particularly within the unique lung microenvironment, in a disease context. We will define the benefits of small molecule ‘efferocytosis boosters’ in inflammatory lung disease, notably using unique clinically relevant models of COPD and severe asthma.

FOR Codes: Immunology, Medical And Health Sciences, Biochemistry and Cell Biology not elsewhere classified, Respiratory Diseases, Health, Respiratory System and Diseases (incl. Asthma)