The Role of Toll/IL-1 Receptor (TIR)-Signalling "Checkpoint" Regulators in Pathobiology of AMD

Summary

The inflammatory response is needed to take care of all the tissues that make up our body to keep us in working order. However inflammation is a double-edged sword: too much can cause damage to the surrounding tissues, and too little can be ineffective at inducing healing. To overcome this problem, the inflammatory response has evolved so that once a pro-inflammatory response is generated, it promotes the expression of chemicals that provide feedback and switch off inflammation by inhibiting the very pro-inflammatory signals that generated them; in this way, the process of inflammation programs its own end. Age-related macular degeneration (AMD) has elements that indicate that the inflammatory response is uncontrolled and persistent when low-level inflammation is observed. Our research question asks whether this active process of switching off the inflammatory response is lost in people with AMD.

Project Details

My lab aims to understand the underlying mechanisms that are the driving forces behind age-related macular degeneration (AMD) so that we can prevent macular degeneration in future generations and stop its progression in those currently suffering with this blinding disease. The overarching goal of this proposal is to investigate the contribution that “negative-regulators” of toll-like receptors (TLRs) play in the pathogenesis of AMD.

TLRs are critical sensors of danger used by our immune system. First we will analyze expression levels of a range of negative-regulators of TLRs in our circulating immune cells and in the retinas of AMD and healthy donors. Second, we will analyze the impact of a pro-inflammatory or anti-inflammatory state on negative regulators of TLRs. Third, we will investigate the role of negative-regulators of TLRs in the eye’s ability to protect itself from overt inflammation. Finally we will analyze a role for negative regulators of TLRs in controlling intracellular inflammatory signaling pathways in immune cells in the environment of the eye.

It is clear that inflammatory processes are involved in some capacity in the pathogenesis of AMD. Despite this, there has been scant investigation into the role of TLRs, the primary initiators of inflammation, in AMD, outside of nominal genetic risk factor association studies and expression analysis. To the best of my knowledge, no one has yet tackled the role that TLR-inhibitory proteins may play in pathogenesis of AMD. Early disease is often asymptomatic, and that by itself represents a significant challenge, making it more difficult to recruit people who are only beginning to develop AMD into studies. Nonetheless, such studies have the potential to offer insight into the mechanisms at play both in initiating the disease and driving it forward.

For this project, we will use peripheral blood mononuclear cell (PBMCs) already banked from a population cohort that investigates the ageing process on the island of Ireland. Those diagnosed with AMD are at the early stages of disease. This is key to the potential success, uniqueness, and feasibility of the proposed research. Using these samples we will be able to determine the mechanisms at play in at the earliest stages of disease, and to minimize confounding symptomatic factors.

This research will expand our knowledge of the role of inflammation in early stage AMD and provide insight into possible interventions that may have potential to be disease modifying. Ideally, identification at the molecular level of “checkpoints” of the inflammatory response in AMD will yield novel therapeutic approaches, in the form of agents that might either block or induce TLR signaling events.