Age related macular degeneration (AMD) is the leading cause of sight loss in Ireland and the developed world for over 50s. There are two types- neovascular (wet) AMD and non- neovascular (dry) AMD. This is a multifactorial disease in which age is the primary risk factor. There currently is no FDA approved treatment options for dry AMD, which is the more common form of the disease.
The ageing process is driven by senescence, a process that causes chronic but low-level uncontrolled inflammation and decreased tissue repair. Senescence leads to cellular dysfunction and spreads to neighbouring cells through the release of senescence associated secretory phenotype (SASP), composed of pro-inflammatory cytokines.
The blood retinal barrier is composed of two layers: the inner blood- retinal barrier (iBRB) and the outer blood retinal barrier (oBRB), held by junction proteins such as claudin-5. SASP has been associated the impairment of the iBRB and oBRB. The dysregulation of the retinal barrier makes them more permeable to peripheral immune cells, which is linked to retinal degenerative diseases. Most studies related to AMD focus on the oBRB, although the dysregulation of the iBRB has shown to play a key role in retinal degeneration. We hypothesise that age-associated inflammation causes the dysregulation of the iBRB and contributes to the pathophysiology of AMD.
This project aims to discover the extent to which SASP mediated inflammatory response impairs iBRB function. We will use Human Retinal Microvascular Endothelial Cells (HRMECs) as a model for the retina in vitro. The integrity of the iBRB in response to SASP will be tested using a variety of techniques: transepithelial electrical resistance (TEER), flux assays, flow cytometry and confocal microscopy.
My proposal to characterize the role of ageing on the iBRB will improve the understanding of the pathophysiology of AMD and outline possible therapeutic targets.
