Interpericyte tunneling nanotubes as new therapeutic targets for neurovascular recovery and vision restoration in glaucoma. - PROJECT SUMMARY Glaucoma patients suffer from major vascular deficits, but the mechanisms underlying blood flow abnormalities, and whether they can be reversed, are not known. Our long-term goal is to develop innovative strategies that promote neurovascular health and restore vision in glaucoma. The primary objective of this proposal is to determine the mechanisms leading to glaucoma-induced damage of interpericyte tunneling nanotubes (IPTNTs), highly specialized structures that connect two pericytes and are essential for blood flow regulation in the retina and optic nerve. The central hypothesis is that signals from the microenvironment, notably surrounding glia and retinal ganglion cells, act on IPTNT-linked pericytes to modulate calcium dynamics and blood flow; and that disruption of these pathways cause vascular abnormalities in glaucoma. The rationale underlying this proposal is that completion will identify key molecular targets for protecting or regenerating IPTNTs, which will improve blood supply and support neuronal function. The proposed work will also develop a widely-applicable live imaging platform to gain unique insights into how vascular defects affect retinal ganglion cell function during glaucomatous stress. Our central hypothesis will be tested by pursuing three specific aims: 1) determine the role of glia-derived S100β in IPTNT damage; 2) determine whether dysregulated adenosine signaling in neurons and/or glia disrupts IPTNT-mediated capillary dynamics; 3) establish the efficacy of platelet-derived growth factor BB as a strategy to regenerate IPTNTs. We will pursue these aims using well-established glaucoma models in mice (aims 1-3) and non-human primates (aim 3) as well as an innovative combination of cellular, genetic, and molecular tools with cutting-edge live imaging technologies using clinically relevant endpoints. The proposed research is significant because it will determine the critical mechanisms that support IPTNT structure and function and, therefore, have potential as therapeutic targets for glaucoma. It is also significant because using both mice and non-human primates will generate rigorous and compelling pre-clinical data that will serve as a knowledge-translation springboard for clinical development. This work will also develop foundational resources that may be used by other glaucoma researchers. The expected outcome of this work is a better understanding of the molecular underpinnings of blood flow insufficiency in glaucoma. The results will have an important positive impact because they will identify molecular targets for further clinical development thus expanding treatment options for glaucoma and other neurodegenerative diseases associated with vascular deficits.
