MAPRE3

A new compound potentially could offer an alternative to injections for the millions of people who suffer from an eye condition that causes blindness. A new compound developed at the University of Illinois Chicago potentially could offer an alternative to injections for the millions of people who suffer from an eye condition that causes blindness. Wet age-related macular degeneration causes vision loss due to the uncontrolled growth and leakage of blood vessels in the back of the eye. A new paper in Cell Reports Medicine led by UIC researcher Yulia Komarova finds that a small-molecule inhibitor can reverse damage from AMD and promote regenerative and healing processes. The drug can also be delivered via eyedrops -- an improvement over current treatments for AMD, which require repeated injections into the eye. "The idea was to develop something that can be more patient-friendly and doesn't require a visit to the doctor's office," said Komarova, associate professor of pharmacology at UIC. Komarova's compound targets a protein called End Binding-3 in endothelial cells, which line the inside of blood vessels. In the new study, the researchers looked at whether inhibiting EB3 function could stop the damaging leakage associated with wet AMD. Using computational drug design methods, the team developed a small inhibitor that could be delivered externally via eyedrops instead of by injection. They then tested its effectiveness in animal models of wet AMD, finding that twice-daily treatment reduced eye damage within 2 to 3 weeks. Further investigation found that the inhibitor worked by rolling back aging-related genetic modifications. Aging causes inflammation and hypoxia in the eye that leads to changes in gene expression associated with the cellular effects and symptoms of wet AMD. Komarova and colleagues found that the EB3 inhibitor they developed reversed these epigenetic changes, restoring gene expression to a normal, healthy state. "We reduce the effects of the stressor on endothelial cells and we improve regenerative processes, accelerating healing," Komarova said. "That can be tremendous for the function of the cells." Because blood vessel leakage and hypoxic stress also drive many other medical conditions, Komarova's group is interested in testing the inhibitor in models of acute lung injury, diabetic retinopathy, stroke, heart disease and even the general effects of aging on the brain. They're also exploring whether an implantable lens, similar to a contact lens, could deliver the drug to the eye more effectively than eyedrops. In addition to Komarova, UIC authors on the paper include co-first-authors Quinn Lee, Wan Ching Chan and Xinyan Qu, as well as Ying Sun, Jonathan Le, Uzma Saqib, Mitchell Y. Sun, Kevin Kruse, Avik Banerjee, Ben Hitchinson, Melissa Geyer, Fei Huang, Victor Guaiquil, Amelia A. Mutso, Dr. Mark Rosenblatt, Mark Maienschein-Cline, Vadim Gaponenko and Asrar Malik.

Cancers, degenerative diseases: deregulation of our cells' internal communication pathways is at the root of many conditions. Microtubules -- microscopic protein filaments -- play a crucial role in controlling these exchanges. However, their mechanisms remain poorly understood. A team has identified a new mechanism, involving two proteins, that governs their growth. The discovery opens up unprecedented prospects for the development of new treatments that can act at the very heart of cells. Cancers, degenerative diseases: deregulation of our cells' internal communication pathways is at the root of many conditions. Microtubules -- microscopic protein filaments -- play a crucial role in controlling these exchanges. However, their mechanisms remain poorly understood. A team from the University of Geneva (UNIGE) has identified a new mechanism, involving two proteins, that governs their growth. The discovery opens up unprecedented prospects for the development of new treatments that can act at the very heart of cells. These results are published in the Proceedings of the National Academy of Sciences (PNAS). As a city needs fluid transport networks for its exchange and development, so cells need internal microscopic ''roads'' to supply themselves, grow and divide. These ''roads'' are called ''microtubules''. They are long protein filaments that form the backbone of the cell. Problems with their regulation can cause diseases such as cancer and neurodegenerative disorders. Understanding how they work -- and in particular the mechanisms that control and regulate their growth -- is therefore crucial. Although significant advances have been made in this field over the last forty years, the complexity of this system continues to require intense research. Two key proteins Recent work by Charlotte Aumeier, assistant professor in the Biochemistry Department at the UNIGE Faculty of Science, provides new insights into the functioning of the microtubule. It shows how two specific proteins, CLIP-170 and EB3, undergo liquid-liquid phase separation at the tip of the microtubule during its growth. In other words, these two proteins separate from the cellular liquid medium to form a second liquid phase at the tip of the microtubule, like a drop of oil in water. Microtubules are dynamic structures that continually build and deconstruct themselves. ''This phenomenon of phase separation, at the level of the microtubule, increases the concentration of proteins, including tubulin, and significantly stimulates the growth rate of microtubules while reducing depolymerisation events, i.e. microtubule decay events,'' explains Charlotte Aumeier, the last author of the study. This mechanism therefore seems to control the dynamics of cellular microtubules in a very concrete way. Joint Action Julie Miesch, a PhD student in Charlotte Aumeier's laboratory and first author of the study, explains that ''it is the synergy between CLIP-170 and EB3 that ensures the regulation of microtubule growth, thanks to a liquid-liquid phase separation mechanism''. Taken individually, CLIP-170 has no interaction with tubulin. As for EB3, although it is capable of interacting with tubulin, it only forms tiny aggregates on the surface. The combination of these two proteins makes it possible to regulate the speed of microtubule growth locally. The role of these two proteins was observed by in vitro and then in cellulo measurements using a combination of two methods, total internal reflection fluorescence microscopy and high-throughput confocal microscopy, available at the UNIGE within the ACCESS GENEVA platform. These results highlight a new level of regulation in the control of microtubule dynamics. This opens up the possibility of new targets in the development of new anti-cancer therapies. This breakthrough promises to further broaden our understanding and our ability to act at the very heart of cellular processes.