The responsiveness of anti-VEGF therapy and monocyte function in neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Neovascular AMD (nvAMD), which accounts for 90% of cases of AMD-related vision loss, is treated by the intravitreal injection of anti-vascular endothelial growth factor-A (VEGF-A) antibody. The therapy can stabilize disease progression and even improve vision. However, there is a huge variation on the responsiveness to the therapy, and a significant proportion of our patients do not respond to treatment. For those who respond well, some will develop macular geographic atrophic changes (i.e. dry-AMD). We believe that the variability in angiogenic growth factor production by blood cells may be related to the responsiveness of the patients to anti-VEGF-A therapy. In collaboration with Professor Usha Chakravarthy, in this study, we will examine monocyte angiogenic growth factor production in nvAMD patients and will investigate how this is related to patients’ response to anti-VEGF therapy. The results will help clinicians to predict anti-VEGF therapy responsiveness in nvAMD patients and improve clinical service.

Funding Source: Dunhill Medical Trust

Researcher: Dr Judith Lechner (Post-Doctoral Research Fellow)

 

The role of monocytes and complement activation in age-related macular degeneration   

Inflammation is believed to play a pathogenic role in AMD, although the precise mechanisms remain ill-defined. Environmental factors such as cigarette smoke, sunlight exposure and high-fat diet may cause damage to retinal cells and such damage accumulates with age. Damaged cells/molecules are to be removed and replaced to maintain functionality. The immune system plays an important role in repairing tissue damage and maintaining homeostasis. We hypothesize that AMD results from an imbalance between the level of macular dysfunction caused by old age and environmental factors and the capacity of the immune system to rectify tissue damage without escalation to overt pathology. The overall objective of this project is to understand the detailed immune pathways that are involved in rectifying retinal damage caused by environmental factor and old age, and how the pathways are altered in AMD. The knowledge will be crucial to the further development of target-specific immune therapy for AMD.

 

Funding Source: Fight for Sight

Researchers: Dr Rosana Penalva (Post-Doctoral Research Fellow)

 

The influence of cataract surgery on the initiation and progression of diabetic retinopathy

Diabetic retinopathy (DR) is the major cause of blindness in western countries although the pathogenesis of the disease is not fully understood. Inflammation is believed to be involved in the initiation and progression of the disease. Cataract surgery is the most common procedure conducted in the eye clinic. Evidence from clinical epidemiological studies has shown that cataract surgery increases the risk and worsens the progression of DR. Our preliminary study has shown that cataract surgery induces massive pro-inflammatory cytokine/chemokine expression and complement activation in the retina (Xu, et al. IOVS. 2010). In this project, we aim to understand how cataract surgery might affect DR initiation and progression.

 

Funding Source: Diabetes UK

Researcher: Dr Jose Romero (Post-Doctoral Research Fellow)

 

Microglial activation in diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of blindness among the working population in developed countries.  Inflammation is known to play an important role in DR pathogenesis although the detailed pathways and inflammatory mediators involved remain poorly understood.  Microglia are resident retinal innate immune cells and provide the first line of defense to retinal tissue under exogenous and endogenous insult conditions.  Microglial activation has been detected in diabetic retina, and activated microglia may contribute to DR pathogenesis by secreting pro-inflammatory cytokines.  This project aims to understand the molecular cues that control microglial activation under diabetic conditions.

 

Funding Source: Development of Employment & Learning (DEL)

Researcher: Miss Lisa Goodman (PhD Student)

 

Complement and microglial activation in age-related retinal degeneration

Pathologies (drusen, atrophy, and neovascularisation) in AMD primarily occur at the retina-choroidal interface. Previously we have shown that retinal ageing is accompanied by a number of para-inflammatory changes, including activation and accumulation of macrophage/microglia at the subretinal space, and complement activation at the retina-choroidal interface (Chen et al. 2008; Xu et al. 2009). We believe that this type of para-inflammatory response is important for retinal homeostasis and should be beneficial for the ageing retina. Dysregulated para-inflammatory response may contribute to AMD pathology. The aim of this project is to understand how the complement system is activated at the retina-choroidal interface and the contribution of microglia/macrophages on complement activation.

 

Funding source: Age UK (Research into Ageing)

Researcher: Mr Chang Luo (PhD Student 2009-2012)

 

Mechanisms of chronic inflammation-mediated retinal angiogenesis
Chronic inflammation and angiogenesis are coupled together in many clinical settings. Long-standing chronic inflammation may induce angiogenesis, which then further promotes chronic inflammation. Neovascualr AMD and proliferative diabetic retinopathy are well-documented angiogenic retinal diseases, and low-grade chronic inflammation is an important component of the pathogenic event in these conditions. Furthermore, neovascular membrane is a common cause of acute visual loss in patients with chronic retinitis/choroiditis. We have shown recently that chronic inflammation in experimental autoimmune uveoretinitis (EAU) induces retinal angiogenesis (Chen, et al. Am J Pathol. 2012). The model offers unique opportunities to usefully interrogate disease mechanism and assess therapeutic strategies that combat underlying inflammatory drive contributing to generation of neovascular membrane in various retinal diseases.  

 

Funding Source: National Eye Research Centre

Researcher: Mr Jiawu Zhao (PhD Student)

 

MicroRNA in retinal ageing and age-related retinal degeneration

MicroRNAs are post-transcriptional regulators that bind to complementary sequences on target mRNA resulting in translational repression and gene silencing. MicroRNAs have been shown to play important roles in various human diseases. In collaborating with Dr David Simpson, we are investigating the role of microRNA in retinal ageing and age-related macular degeneration.

Funding Source: Queen’s University Belfast

Researcher: Miss Sudha Priya (PhD Student)