Mechanisms Controlling Non-Uniform Aqueous Humour Drainage
MentorDarryl Overby, PhD
The goal is to understand if VEGF signaling mediates changes in segmental outflow patterns in response to metabolic demands and whether glucocorticoids impair this mechanism.
The outflow segmentation cycle proposes that VEGF expression in the trabecular meshwork (TM) increases in response to hypoxia or metabolic stress in areas of low aqueous humour flow. VEGF then acts on the inner wall to increase local outflow conductivity and nutrient delivery by aqueous humour. We hypothesize that these dynamic changes are representative of a healthy TM. Therefore, disruption of the segmental outflow cycle by glucocorticoids, might lead to TM dysfunction and ocular hypertension, as glucocorticoids are known to interfere with VEGF signaling. We will use mouse models to test these hypotheses. We are showing for the first time that segmental outflow patterns are dynamic and change over time in young, healthy mice, as such, there must be mechanisms controlling it. The proposed outflow segmentation cycle puts together in a big picture different mechanisms that have been already implicated in outflow regulation: VEGF signaling and metabolic activity. We know these processes play a role in normal outflow function, but we do not know how and why. The knowledge we would gain from this project would contribute to understanding how aqueous humour outflow resistance and IOP are regulated. The lack of understanding of how outflow resistance is controlled is the main reason for not having effective therapeutics to lower IOP and treat glaucoma. Additionally, the information gained using the glucocorticoid-induced ocular hypertension model would translate into understanding why outflow becomes impaired. Glucocorticoids are one of the most prescribed drugs, and elevated IOP is a well-defined side effect.