Modulation of selective autophagy to treat Vascular Ehlers Danlos Syndrome

My laboratory studies the cellular mechanisms involved in degradation/removal of toxic molecules from the cells. The identification of such mechanisms holds the potential to modulate cellular clearance and promote cellular fitness by preventing the accumulation of cellular "garbage". Activation of cellular clearance might be particularly important to prevent the accumulation of proteins that form aggregates due to mutations in their coding genes. In such cases disease manifestations may result from: 1) the lack of the functional protein and 2) toxic effects of the aggregates. The lysosome is the main degradative organelle of the cell and intracellular substrates to be degraded are targeted to the lysosomes via autophagy. Autophagy can also targets fragments of endoplasmic reticulum (ER) to the lysosomes for degradation. Ehlers-Danlos syndrome (EDS) are disorders that affect connective tissues supporting the skin, bones and blood vessels. Vascular Ehlers Danlos EDS (vEDS) is caused by mutations in COL3A1, that encodes the alpha 1 chain of type III collagen, a major extracellular matrix component of the vasculature and hollow organs. Mutant collagen accumulates in the ER and eventually causes ER-stress and dysfunction, that also contribute to disease manifestation. In this application we intend to explore whether the degradation of ER via autophagy can be exploited to promote degradation of aggregate collagen molecules in vEDS cells. We expect that enhancing the autophagy of the ER will increase degradation of collagen aggregates and in turn restore ER homeostasis and function. We expect that this approach will be beneficial for patients affected by vEDS.