Title: Dissecting the role of the mTORC/AMPK axis in neutrophil mediated lung injury
Funder: The Academy of Medical Sciences

Abstract: The aim of this project is to investigate the role of AMP-activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) in neutrophil mediated inflammation. Neutrophilic inflammation is implicated in a number of respiratory diseases, including acute respiratory distress syndrome (ARDS). AMPK and mTORC1 act to sense and respond to the metabolic environment, directing cell growth, proliferation and survival. Both AMPK and mTORC1 interact with hypoxic signalling pathways, driven by the hypoxia inducible factor (HIF) and its regulatory prolyl-hydroxylases (PHDs). Our group and others have shown that hypoxia is a critical regulator of neutrophilic inflammation. Work from my PhD has shown that the hyperinflammatory neutrophil response observed in hypoxia is driven in part by metabolic adaptations which allow neutrophils to engulf and catabolise extracellular proteins to use as a source of energy and amino acids for ongoing protein synthesis. Thus, metabolic alterations play a role in driving neutrophilic inflammation. I propose that AMPK and mTORC1 will therefore be critical regulators of neutrophilic inflammation. Using blood neutrophils from healthy human controls and patients with acute respiratory distress syndrome (ARDS) I will characterise the expression and regulation of AMPK and mTORC1 in neutrophils in health and disease. Secondly, using myeloid cell specific AMPK-alpha knock-out mice, I will investigate the role of AMPK in neutrophilic inflammation in vivo utilising a mouse model of ARDS. Ultimately, this work aims to identify novel therapeutic targets for modulating harmful neutrophilic inflammation, without over-suppressing essential innate immunity.

Lay abstract: Neutrophils are a type of white blood cell essential for fighting infection. However, when activated inappropriately, they can cause diseases such as adult respiratory distress syndrome (ARDS). This results in failure of lung function and low oxygen levels. This project aims to investigate why neutrophils malfunction in this context and to identify new ways to stop the harmful effects of neutrophils without losing the capacity to fight infection. An important factor in determining how cells behave is their access to energy in the form of sugars and amino acids (which build proteins). Cells sense and respond to signals about energy via two proteins: AMP activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). AMPK is active when energy levels are low and drives cells to break down molecules, generating energy. Conversely, mTORC1 is active when fuel is abundant and stimulates cell growth. Relatively little is known about these pathways in neutrophils and I aim to investigate their role in regulating neutrophilic inflammation. I will compare the activity of each pathway in the neutrophils of healthy people and ARDS patients and measure how nutrient and oxygen levels alter activity levels. I will use mice which have been genetically modified to lack AMPK in their neutrophils (“knock-out” mice) to investigate how switching off this pathway alters the inflammatory response as a whole by causing ARDS in knock-out and normal mice and assessing the extent and duration of lung injury. Ultimately, I hope to identify new treatments for ARDS.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM