Mechanisms Controlling Non-Uniform Aqueous Humour Drainage

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 front of the eye is filled with a blood-like but transparent fluid called aqueous humour. Aqueous humour serves two main purposes, it provides nutrients and oxygen to the cells and maintains intraocular pressure (IOP). Aqueous humour circulates constantly, and it drains out of the eye via the outflow pathway. If the outflow pathway gets blocked, aqueous humour cannot easily leave the eye and it builds up, which leads to increase IOP and vision loss due to glaucoma. Our understanding on how aqueous humour is drained is limited, but we know that drainage is not uniform in all areas of the outflow pathway. Thus, areas that do not receive much aqueous humour flow will not receive nutrients. We believe that cells in the outflow pathway can sense that they are starving and have mechanism to redirect flow towards them to be fed. If cells do not receive enough nutrients, they cannot function properly, and aqueous humour cannot be drained as effectively. This might happen as a side effect of treatment with corticoids, which are extensively prescribed and are known to induce elevated IOP in some patients, and especially to those who have glaucoma already. This project will contribute to understanding aqueous humour drainage better, which would help the development of more effective drugs to lower IOP and treat glaucoma.

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 mechanism that have been already implicated in outflow regulation: VEGF signalling 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 understand 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.