Clark Lab

Molecular mechanisms driving age-related macular degeneration

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Scientific Results

The Clark lab has collectively contributed to a number of advancements in our understanding of ocular immunity and the regulation of complement turnover in the extracellular matrix (ECM). None of these achievements are possible in isolation and demonstrates the power of collaborative study, bringing together diverse teams and techniques to answer specific biological questions.


Role of factor H-related (FHR) proteins in driving inflammation in AMD

The genetic risk for developing age-related macular degeneration (AMD) that resides in and around the CFH gene on chromosome 1 has for many years been assumed to directly affect the complement regulator(s) FH and/or FHL-1. Yet after a large international collaborative study lasting four years we showed that in fact the major genetic risk and protective variants for AMD altered not the CFH gene, but the transcription of genes downstream of CFH on chromosome 1: the five CFHR genes. The five FHR proteins made by these genes are significantly elevated in the blood of people carrying genetic risk for AMD, while being significantly lower in people considered protective from AMD. Monitoring circulating FHR levels serves as a potentially powerful tool in the stratification of patients most suited for complement inhibitory therapeutics. Also, this work identifies targeting the circulating FHR proteins as a potential therapeutic strategy.



Bruch’s membrane makes a significant contribution to retinal homeostasis

The acellular membrane underneath the human retina, called Bruch’s membrane (BrM), had been thought of in the past as simply an inert scaffold on which the RPE cells grew. However, work from members of the Clark lab showed that the permeability of BrM is much more selective than previously thought and itself creates two immunologically distinct regions within the eye. Also, the health and composition of BrM directly affects the gene transcription and protein secretion profiles of the adjacent RPE cells, who adhere to BrM through various cell-surface receptors such as the integrin receptors. This work highlights the need to better understand this RPE/BrM interaction and how age-related changes to this unmask underlying genetic risk for ocular disease     



Understanding the mechanism behind complement regulation on ECM

A number of complement-mediated diseases manifest on, or within, the ECM: in the kidney, eye, brain and liver. The soluble complement regulator FH is primarily responsible for protecting these acellular structures from inappropriate complement attack. FH recognises and anchors to these ECM through binding sugar molecules, referred to as GAGs. Members of our lab identified the different GAG structural features recognised by different regions of FH. This explained the influence of specific FH mutations affecting specific organs within the body, and led to the proposition of a ‘GAG Zip-code’ that directs innate immunity on acellular structures.



Translation of scientific discoveries for the benefit of patients

All of the work we do in the lab is for nothing, if it is not for driving real benefit for patients in the future. The vast majority of what we do, discover, and invent contributes primarily to scientific understanding and knowledge. But on those occasions where new potential therapeutics or diagnostics are envisioned, we drive their translation through the protection of IP and development with industrial partners/patient groups. One such example is the creation of Complement Therapeutics Limited (CTx), a company founded to turn powerful new insights in the complement system into innovative treatments for eye, kidney, CNS and systemic diseases.