Overview
Diabetic retinopathy is a common complication of diabetes. It happens when the body’s immune system becomes over-active in response to damage from high blood sugar. The immune response (inflammation) can trigger unhealthy blood vessel growth in the light-sensitive part of the eye (the retina) and this can lead to significant sight loss.
Inflammation is usually tightly controlled by various substances in the body that can put the brakes on the immune system. One such substance is called SIGIRR. Research has shown that animals with cancer, asthma and arthritis have uncontrolled inflammation and worse symptoms if they don't have SIGIRR. However, having excess SIGIRR reduces inflammation.
The researchers think that having too little SIGIRR could be a key part of developing diabetic retinopathy. They have already found that high blood sugar reduces SIGIRR, so in this project they want to find out if targeting SIGIRR can prevent, delay or halt diabetic retinopathy.
Results from this pre-clinical project should give us important information on SIGIRR’s role in diabetic retinopathy including whether gene therapy to increase SIGIRR can protect the retina. If so, this could lead to earlier treatment for people with diabetic retinopathy.
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Scientific summary
Taming inflammation via the SIGIRR pathway for the management of diabetic retinopathy
Diabetic retinopathy (DR) is characterised by progressive microvascular and neuroglial dysfunction leading to retinal ischaemia and degeneration. Inflammation plays a key role in DR development and progression. Inflammation is a protective response of the host against endogenous/exogenous insults. Why it becomes detrimental in diabetes remains poorly defined. The single immunoglobulin IL-1 receptor related molecule (SIGIRR) is an important negative regulator of Toll-like receptor (TLR) and IL-1R signalling pathways and critically controls a variety of innate immune responses.
The team has found that diabetes down-regulates SIGIRR expression in a number of tissues/cells, including the retina, spleen, circulating monocytes and macrophages, and these effects are associated with increased TLR/IL-1R expression and NFκB activation. They hypothesise that insufficient expression of SIGIRR in diabetes results in dysregulated and detrimental inflammation, and that enhancing SIGIRR expression may be a novel approach for therapy.
The project's aims are (1) elucidate the dynamics of SIGIRR expression in diabetic retina; (2) investigate the role of SIGIRR in diabetes-induced inflammation and DR progression; (3) explore the therapeutic benefits of enhancing SIGIRR expression in DR through gene therapy. These are being accomplished through advanced molecular and immunogloical techniques applied to in vitro and in vivo diabetic retinopathy models.