Investigating the regulation of neutrophil protein synthesis and its role in inflammation to identify therapies for inflammatory lung disease

Neutrophil driven tissue injury is a common feature of inflammatory lung disease.

I have shown that tissue neutrophils are biosynthetically active and utilise extracellular proteins to fuel de novo protein synthesis.

The neutrophil proteome is highly dynamic, with protein turnover regulating key process and defining effector functions at sites of injury. The mechanisms which determine the repertoire of neutrophil protein synthesis are unknown.

The requirement for ATP and amino acids suggests a role for the nutrient-sensing kinases, AMPK and mTORC1 and the related proteolytic organelle, the lysosome. mTORC1 and AMPK respond to environmental signals in a cell-specific manner to permit or restrain growth. Neutrophils are non-proliferative but synthetically active cells and, as such, are subject to unique growth pressures.

The role of the mTORC1/AMPK/lysosome axis in responding to these pressures and the factors downstream of them which drive protein synthesis in the neutrophil are unknown. I hypothesise that delineating these pathways will identify novel therapeutic targets in neutrophilic inflammation. My key aims are therefore to: 1.

Determine the factors which regulate neutrophil protein synthesis 2. Investigate the relationship between protein synthesis and inflammation in the neutrophil 3. Target protein synthesis in tissue neutrophils to alter outcomes in inflammatory lung disease