Deciphering the role of macrophages in retinal fibrosis secondary to neovascular age-related macular degeneration

Brief Lay Background

Age-related macular degeneration (AMD) is the loss of central vision resulting from damage to the macula. The macula is a concentrated area of light-sensitive cells at the back of the eye (in the retina).

There are two types of AMD. Dry AMD progresses more slowly, whereas wet AMD (also called neurovascular AMD) can progress rapidly to severe disease and sight loss.

What problem/knowledge gap does it help address

Wet AMD is treated with injections of an antibody into the eye, which can stabilize or even improve vision. But around half of patients who receive this treatment still develop scar tissue in their eye called fibrosis. This fibrosis is what ultimately may lead to sight loss.

The mechanism that leads to fibrosis is currently unclear and there are no treatments to prevent it happening. However, it is thought that inflammation contributes to the process.

This PhD studentship project will explore the role of inflammatory cells called macrophages. Different types of macrophages have different functions when tissue damage occurs. At an early stage they promote inflammation and fibrosis and, later, they may suppress inflammation and start to permanently remodel tissue, such that it loses its function.

A second set of inflammatory cells are called monocytes and these are the precursors for different types of macrophages. Which type of macrophage they turn into is determined by the type of monocyte and the surrounding molecules that stimulate them.

This project will establish exactly how monocytes and macrophages are involved in the build-up of scar tissue in the retina at different stages of wet AMD.

Aim of the research project

The aims of the project are to:

1. Understand the role of macrophages in fibrosis in the retina and at different stages of wet AMD.
2. Understand which subsets of monocytes produce anti-inflammatory and pro-inflammatory macrophages at different stages of wet AMD.
3. See whether fibrosis can be preventing by manipulating which types of macrophages can enter the macula.

This award will also contribute to building capacity in AMD research as it will lead to a PhD for an early career researcher.   

Key procedures/objectives

1. The student will measure the different types of macrophages in eye tissue samples donated from people with wet AMD at different stages of fibrosis compared with healthy eye tissue to determine the types of macrophages present at each stage of disease.
2. They will then measure the type of macrophages and when they appear at the site of tissue damage in mice with wet AMD.
3. They will collect different types of monocytes from mice and see how these contribute to fibrosis development in a petri dish.
4. Next, they will deplete different types of monocytes in mice with AMD and see how this affects the build up of scar tissue.
5. Finally, they will use drugs that block the action of pro-inflammatory monocytes or enhance the action of anti-inflammatory macrophages to see if they can prevent fibrosis.  

Potential impact on people with sight loss

This project will show whether macrophages could potentially be targeted with treatments to prevent the build-up of scar tissue in wet AMD. Similar treatments are already in clinical trials being tested for liver fibrosis, so if this project Is successful, it means there are already drugs ready to test in clinical trials with patients with wet AMD. Ultimately, this could lead to a much-needed treatment for preventing the sight loss associated with wet AMD.