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Retina section from the autophagy reporter (green) mouse, where mitochondria are in labelled red and nuclei are in labelled blue.
Our lab uses cellular and animal models to understand the physiological roles of autophagy and its implications during disease. Autophagy is an essential intracellular degradation pathway that recycles cell components generating new building blocks and energy to maintain cellular homeostasis. Autophagy plays an important role in the response to nutrient starvation; the recycling of damaged organelles and is a survival mechanism under stress conditions.
We are interested in the relationships between autophagy and basic processes such as proliferation, differentiation and cell death to gain insight into development and physiological aging. We want to understand how the selective removal of organelles via autophagy, such as mitophagy and pexophagy impacts the physiology of our cells and how these selective processes are regulated in vitro, in vivo and in animal models of neurodegenerative and diseases. We also seek to identify new therapies that target autophagy pathways by screening for new autophagy-modulating drugs with a view to discovering new treatments for human diseases.
How the complex functionality of the nervous system arises from a pool of undifferentiated neuroepithelial cells during embryonic development is a fascinating process. We are investigating the role of autophagy in the development of the central nervous system in the mouse retina. Some autophagy deficient mice show developmental alterations that result in embryonic lethality. However, it remains unclear why autophagy is essential for proper development. We are investigating the relationship between autophagy and basic processes such as cell proliferation, differentiation, or death. Our data demonstrate that the metabolic activity of autophagy is essential to ensure proper neural differentiation in vivo and in vivo. Our research indicates that the autophagy pathways play multiple roles during embryonic development.
We have shown that selective mitochondrial degradation, a process known as mitophagy, regulates metabolic reprogramming during neurogenesis and mitophagy deficient animals display alterations in neuronal differentiation. In addition, this role of mitophagy in regulating the metabolism seems universal since it is also observed during the polarization of macrophages to a proinflammatory phenotype. We want to understand in precise molecular regulation of mitophagy and its links to metabolism under physiological and pathological conditions.
Our laboratory is very interested in understanding how lysosomes and autophagy play a role in physiological aging. We have shown that in the aged retina there is a decrease in the cells' ability to induce autophagy and that this correlates with night vision loss and the death of light-sensitive cells, the photoreceptors. We have shown that this phenotype is very similar to that observed in the retina of autophagy-deficient animals and is also observed during retinal aging in humans.
On the other hand, our studies show that autophagy deficient animals have a phenotype of accelerated aging being more susceptible to age-associated diseases, such as glaucoma and age macular degeneration. Our research focuses on understanding what are the alterations both at the cell and tissue level that accelerate this susceptibility. Our aim is to search for new therapeutic targets that can be used for these and other age-associated diseases
Defective proteostasis is one of the hallmarks of aging cells and tissues. Of the different components of the proteostasis network, we are interested in autophagy and its changes with age in retina. We have previously shown that, out of the different autophagic pathways that co-exist in all mammalian cells, macroautophagy is the first that declines with age in the retina. A crosstalk between macroautophagy and chaperone mediated autophagy (CMA) has been described whereby, in aged mice retinas, the decrease in macroautophagy correlates with increased CMA. Our working hypothesis is that aged and degenerated retinal cells increase CMA to compensate for macroautophagy loss, in an attempt to maintain cell viability. To test our hypothesis, we use histological and biochemical analysis, but also functional read outs as electroretinogram (ERG) or optic coherence tomography (OCT) and visual behavioral tests. If proven correct, increasing CMA and other selective autophagy pathways such as mitophagy could be a potential treatment to delay consequences of aging in the retina and to ameliorate degeneration in neurodegenerative and age-related retinal pathologies.