Regulation of inflammasome activity by a classic anti-apoptotic protein, XIAP.

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During a lifetime, tissues in our bodies undergo complex homeostatic control to achieve a balance between cell death and survival mechanisms. This is especially key for terminally differentiated, postmitotic cells that do not replicate in adult animals, such as the neurons in the brain and retinal cells in the eye.Our work on the retinal pigment epithelium (RPE), a monolayered postmitotic cell, showed that during aging, the homeostatic mechanisms deteriorate and the RPE succumbs to cellular stress. We showed that a special arm of the immune system, the inflammasome, is present and protects RPE against cell stress. However, for yet unknown reasons, during the aging process, the inflammasome becomes dysregulated and overactive leading to chronic inflammation and eventually RPE cell death. Apoptosis and pyroptosis are two candidate cell death pathways hypothesized to affect the aging RPE. Apoptosis is a programmed death pathway, referred to as “polite cell death,” because the cell slowly shrinks and dies, without disturbing nearby cells. Pyroptosis is another type of programmed death, or “cell death by fire,” in which cells swell, burst and die, causing catastrophic impact to nearby tissues.Our recent work on the RPE revealed that the protein levels of X-chromosome linked inhibitor of apoptosis (XIAP, a key apoptotic inhibitor) and inflammasome activity (a key indicator of pyroptosis) are inversely related. This unique inverse relationship, suggests that the apoptotic and pyroptotic pathways interact at the protein level and modulate each other.The long-term goal of my research program is to understand the interactions between inflammation and cell death pathways at the molecular, cellular and tissue levels in the aging retina. Our specific aims are to understand the detailed biochemical processes that regulate inflammasome activity in vitro (Aim 1). We will assess XIAP's role in inflammasome activity and pyroptosis in vivo (Aim 2). We will evaluate the strategy of bolstering XIAP levels in RPE in order to further probe XIAP's ability to modulate age-related inflammasome activity in vitro and in vivo (Aim 3). The objectives are designed with a significant training component to allow us to prioritize equitable participation by all levels of students, to provide HQP for future employment in academia and industry in Canada. The proposed research program is important; it will advance our fundamental understanding of homeostatic cell function and the relationship between inflammation and cell death. The anticipated outcomes include novel discoveries into the regulatory pathways of inflammation, pyroptosis and apoptosis at the molecular, cellular, and tissue levels of the RPE and retina. These outcomes will be used in broader applications and future studies in cellular stress responses, immune regulation, cell death pathways, and aging in the brain and eye.