Developing Novel Mechanisms to reduce Inflammation in Aging (Inflamm-aging)

Supervisors: Dr Mohini Gray, Prof Mark Bradley

Project description:

Inflammation is a major factor in many conditions that are more prevalent in older people, including cardiovascular disease, arthritis and Alzheimers disease. Chronic inflammation accelerates the degeneration of major organs and hastens death (Chung et al., 2009). 

Inflammatory arthritis, which affects more than 70 million people, results in chronic pain, and disability in older people, costing over $12 billion to treat worldwide. Activated immune cells, including neutrophils and macrophages, release inflammatory proteins called cytokines, which attracts and activates other immune cells, inducing them to release substances, that destroy the joints and tendons (McInnes and Schett, 2011).

When immune cells die by a natural form of cell death called apoptosis, it serves to both remove the inflammatory cells and importantly induces a state of immune regulation. Indeed, the death of neutrophils, that have accumulated at an inflamed site, is a prerequisite for the resolution of an inflammatory response. In our lab we have been working on the mechanism of this immune regulation for some years. We have shown that apoptotic cells induce both pro-resolution macrophages and regulatory B cells

(Brook et al., 2016). We have now identified a natural antibiotic (A23187/Apolip) that has been encapsulated within a liposome. Apolip can safely induce the apoptosis of neutrophils and inhibit inflammatory macrophages. In a model of autoimmune arthritis, we have shown that Apolip has a very marked effect, both preventing and curing inflammation by inducing apoptosis of the innate immune cells responsible for driving it.

In this project we wish to understand how Apolip prevents inflammation. We will optimize the form and delivery of Apolip and identify where it localizes to in vivo. In addition, we will identify (by the histological analysis of joints and the culture of blood and synovial immune cells), how Apolip affects the inflammatory cytokine profile in a model of systemic polyarthritis. We will also study the ability of Apolip to affect pro-inflammatory cytokine secretion and activation of synovial immune cells isolated from patients with inflammatory arthritis by flow cytometry and ELISA. If this drug is effective at resolving chronic systemic inflammatory joint disease we expect it will also be useful in patients with a number of diseases characterized by inflammation, including cardiovascular and lung disease.

This research will lead to an expertise in inflammation biology, in vitro and in vivo immunology techniques and data analysis. In addition, the PhD student will gain important knowledge in chemistry particularly the optimization of drug delivery. The data generated is expected to lead to publications and the opportunity to present data at both immunology and chemistry conferences nationally and internationally.