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Biology of Ageing

The increase in life expectancy in developed countries has led, in recent years, to a significant increase in the prevalence of age-related diseases. For example, estimates predict that by 2050 20% of the population in Europe will be over 65 years old.

The vast majority of eye diseases are age-related. These diseases include cataract, age-related macular degeneration (ARMD) and diabetic retinopathy. The molecular mechanisms underlying many of the pathophysiologic changes associated with such diseases remain to be elucidated but, are likely to comprise both a genetic predisposition and environmental risk factors. Increased production of damaging agents and/or loss of ability of cells to respond to stress are causally related to various age-related diseases.

The Biology of Ageing group is interested in studying the cellular and molecular mechanisms underlying physiopathologic changes related to ageing. Our group has a particular interest in the study of damaged protein repair and/or degradation through the ubiquitin proteasome pathway or chaperone-mediated autophagy. The Biology of Ageing group is also interested in studying how changes in the ubiquitin proteasome pathway can contribute for phenotype changes related to ARMD or diabetes. Another area in which our group is focused upon is the effect of oxidative damage upon intercellular communication and the role of ubiquitin in regulating this mechanism.

Oxidative Damage and Inactivation of the Ubiquitin Proteasome Pathway

Many of the degenerative diseases that afflict vision organs, including ARMD and diabetic retinopathy are associated with increased neovascularization of the retina. Proliferation of endothelial cells and the formation of new blood vessels is, in part, regulated by the transcription factor Hypoxia Inducible Factor (HIF). A major objective of this research unit is to understand the molecular mechanisms and signalling events that may interfere with proteasome-dependent degradation of HIF-1, leading to abnormal retinal vessel proliferation. Our work has already led to the identification of a novel molecular mechanism involved in HIF-1 degradation in diabetes during hypoxia. The identification of this new degradation mechanism for HIF-1 may be crucial for the development of new therapies that prevent retinal neovascularization in diabetes.

In a collaborative effort with national and international partners our laboratory recently demonstrated that inactivation of critical components of the ubiquitin proteasome pathway in retinal pigmented epithelium cells (RPE) may contribute for cellular and phenotype alterations associated with ARMD, including the neovascular component (exsudative form of ARMD) and the inflammatory component. As part of our unit’s future strategy we are already developing transgenic animal models of retinal diseases, that will allow for a better understanding of the role of the ubiquitin proteasome pathway in development and progression of ARMD.

Cellular Lesion and Repair

During ageing there is a progressive accumulation of damaged biomolecules in tissues. Cells possess several pathways for degrading and/or recycling damaged proteins. Our group has already shown that a balance between degradation of ubiquitinylated proteins and molecular chaperones is critical to maintain the biological activity of many proteins. Currently we are carrying out studies to identify communication pathways between the different protein degradation pathways. For example, we speculate that some proteins may be degraded by more than one pathway with the help of specific cellular machinery. It is known that the ability of cells to eliminate damaged or obsolete proteins is a critical factor to ensure cell survival. Studies currently being done in our laboratory show that the formation of specific supramolecular complexes may determine the end destination of obsolete proteins: degradation or repair. For example, chaperone-mediated autophagy was recently identified as a new pathway for selective protein degradation. In this process proteins are directed for degradation in the lysosome by action of molecular chaperones. Currently our laboratory is performing studies that showcase a new mechanism through which different protein degradation pathways, such as the ubiquitin proteasome pathway and chaperone-mediated autophagy, can have interception points which allow substrates to shuttle between pathways.

Intercellular Communication

Gap junctions are protein complexes that allow communication between eukaryotic cells through channels composed of connexins. For example, in the lens, gap junctions are responsible for communication between metabolically active epithelial cells and internal fibres, with reduced metabolic activity. In the retina, electric and metabolic coupling between retinal cells, including neurons, is mediated by gap junctions. Therefore, changes in gap junction intercellular communication induced, for example, by deregulation of connexin degradation mechanisms, may originate many of the pathologies that lead to vision loss, such as cataract, diabetic retinopathy or ARMD.

One of the objectives of our research is the characterization of the molecular mechanism involved in gap internalization and degradation, particularly, the role of ubiquitinylation in regulating connexin intracellular traffic.