PhD Studentship: Deciphering the Role of the Alveolar Lipidome in Modulating Alveolar Macrophage Metabolic Programming in Health and Disease

The unique location of alveolar macrophages (AMs) within the alveolar lumen, exposed to the outside environment, requires these cells to balance inflammatory responses to infection against resolving functions to prevent immune-mediated tissue damage. In health, AMs clear a diverse range of allergens and pathogens, as well as apoptotic cells. AMs are crucial for maintaining alveolar immune homeostasis; the pro-tolerogenic characteristic of AMs have evolved to prevent excessive inflammation in the face of continuous low-level stimulation.

AMs are adapted to the unique alveolar environment and have a distinct metabolic state. Their low glucose high lipid environment dictates their metabolic and functional responses. Glucose concentrations in the alveoli are <10% of those in the blood; AMs exhibit extremely low levels of glycolysis. Instead, AMs upregulate mitochondrial respiration and highly express the peroxisome proliferator-activated receptor gamma (PPARγ), which promotes fatty acid oxidation to fuel oxidative phosphorylation. AMs also undertake catabolism of pulmonary surfactant, a monolayer predominantly composed of polar phospholipids. AM mitochondrial activity and effector functions are influenced by surfactant and the wider alveolar lipidome, which have major implications for AM-mediated immune responses in pulmonary tissue. Dysregulation of mitochondrial activity leads to effector dysfunction and contributes to disease pathology, both acute (e.g. Acute Respiratory Distress Syndrome- ARDS) and chronic (Idiopathic Pulmonary Fibrosis- IPF).

The aims of this project are:
1) Determine the alveolar lipid composition in healthy versus acute/chronic disease states (ARDS, IPF).
2) Determine the role of differentially expressed lipids on alveolar macrophage effector function, phenotype, metabolic profile and mitochondrial dynamics / turnover
3) Determine whether targeting specific enzymes responsible for lipid metabolism can abrogate the metabolic and functional effects on Ams.

Funding notes:

This is a fully funded Biotechnology and Biological Sciences Research Council studentship. Stipend and tuition fees are paid for 4 years as well as there being a budget for project consumables, travel and a laptop to be purchased.

Supervisor(s): Dr Rahul Mahida (r.mahida@bham.ac.uk) and Dr Jose Romero. 

References:

Chen J, Deng JC, Zemans RL, et al. Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection. Nat Commun. 2022 Nov 9;13(1):6759. doi: 10.1038/s41467-022-34593-y. PMID: 36351902.

Nagata K, Hishikawa D, Sagara H, et al. Lysophosphatidylcholine acyltransferase 1 controls mitochondrial reactive oxygen species generation and survival of retinal photoreceptor cells. J Biol Chem. 2022 Jun;298(6):101958. doi: 10.1016/j.jbc.2022.101958. Epub 2022 Apr 20. PMID: 35452679.

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