Investigating the role of Inter-alpha-inhibitor Heavy Chain 3 in 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).

A hallmark of AMD is the build-up of a substance called ‘drusen’. Drusen are made of fat and protein and a type of calcium called hydroxyapatite.

Drusen often build up in a region of the retina called Bruch’s membrane – which forms an important part of the blood-retinal barrier. The blood-retinal barrier is essential for maintaining the health of the eye, and many diseases begin when damage occurs to this barrier. Learning more about how Bruch’s membrane is damaged in AMD is essential to understanding how the disease develops.

What problem/knowledge gap does it help address

Although there are many factors that contribute to AMD, genetics has a strong influence on a person’s risk of the disease. There are 34 different regions of the genome linked to AMD. But although researchers know which genes influence risk, less is known about how these genetic changes lead to AMD.

Dr Clark’s team has previously studied donated eye tissue from people with a specific genetic fault that puts them at risk of AMD. This revealed that a protein called Inter-alpha-inhibitor Heavy Chain-3 (ITHI3) was reduced in Bruch’s membrane at the early stage of disease and increases later once AMD is established.

In this project, a PhD student will expand on this work by looking at ITIH3 in donated eye tissue from people with healthy eyes and from people carrying different genetic faults linked to AMD.

Aim of the project

The student aims to determine whether: 

1. ITIH3 has anti-inflammatory and tissue protective properties in Bruch’s membrane of healthy human eyes
2. Altered levels of ITIH3 in these locations contributes to the initiation and progression of AMD 

Key procedures/objectives

The student will use human eye tissue from the Manchester Eye Tissue Repository (METR). This tissue bank contains more than 1300 samples that have been genetically sequenced. 

The student will carry out three key experiments: 

1. Use microscopy and fluorescent dyes to determine where ITIH3 and associated molecules are located within the eye.
2. Test whether ITIH3 is made within the eye, by determining if it is manufactured by retinal pigment epithelial cells. These cells lie next to the Bruch’s membrane at the outermost surface of the retina.
3. Determine how ITIH3 interacts with other molecules involved in inflammation and damage repair.

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

Potential impact on people with sight loss

Together, these experiments will determine whether ITIH3 is a potential new treatment target for AMD. The student will determine where ITIH3 comes from, what other molecules it interacts with, and the subsequent consequences on AMD. This could lead to a range of potential avenues to explore with new treatments. By providing a clearer understanding of the development of AMD from early to late-stage when patients lose their sight, the project will identify opportunities for slowing or stopping the progression of disease.