Regulation of Capillary Blood Flow in the Choroid Vasculature
The goal of the project is to understand the non-neuronal mechanisms regulating choroidal blood flow and identify new therapeutic targets relating to the pathogenesis of age-related macular degeneration.
Using high-speed and high-resolution spinning disk microscopy and a novel ex vivo pressurized-choroidal vasculature preparation, we will examine how the application of light affects the contractile state of the blood vessels controlling choroidal blood flow. In addition, we will employ a combination of molecular biology, patch-clamp electrophysiology, and super resolution imaging to identify the cellular targets and ion channels responsible in the light-dependent constriction of choroidal blood vessels.
The current proposal will use a combination of novel approaches to test the hypothesis that light stimulates light can affect endothelial cell and mural cell calcium dynamics leading to changes in vascular tone. These approaches include: a novel ex vivo pressurized-vasculature preparation; new transgenic mice expressing fluorescent calcium biosensors; and choroidal tissue from Cynomolgus monkeys. Conceptual innovations include the concept that K+ efflux as a cellular signaling modality acting on the choriocapillaris as sensory webs responding to the metabolic needs of nearby photoreceptors.
Successful completion of the current proposal will transform our understanding of the function of capillary networks within the choroidal vasculature, establishing these networks as sensors and active contributors to the regulation of local blood flow necessary to meet the unique metabolic demand of photoreceptors of the eye. By building a better understanding of the non-neuronal mechanisms of blood flow control, the proposed work will provide new insights in the pathogenesis of age-related macular degeneration and unearth new pathophysiological targets for therapeutic interventions.