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

*在我们的一生中，我们体内的组织经历复杂的动态平衡控制，以实现细胞死亡和生存机制之间的平衡。这对于成年动物中不能复制的终末分化的有丝分裂后细胞尤其关键，例如大脑中的神经元和眼睛中的视网膜细胞。我们对视网膜色素上皮(RPE)的研究表明，在衰老过程中，动态平衡机制恶化，RPE屈服于细胞压力。我们证明了免疫系统的一种特殊的手臂，炎症体，存在并保护RPE免受细胞压力的影响。然而，由于未知的原因，在衰老过程中，炎症体变得失调和过度活跃，导致慢性炎症，最终导致RPE细胞死亡。细胞凋亡和上睑下垂是两种可能影响RPE老化的细胞死亡途径。细胞凋亡是一种程序性死亡途径，被称为“礼貌细胞死亡”，因为细胞会慢慢收缩和死亡，而不会干扰附近的细胞。上睑下垂是另一种类型的程序性死亡，或“细胞火灾死亡”，在这种情况下，细胞膨胀、破裂和死亡，对周围组织造成灾难性的影响。我们最近在RPE上的工作表明，X染色体连锁的凋亡抑制因子(XIAP，一种关键的凋亡抑制因子)的蛋白水平与炎症肌小体活动(上睑下垂的一个关键指标)呈负相关。这种独特的反向关系表明，凋亡和嗜热通路在蛋白质水平上相互作用，并相互调节。我研究计划的长期目标是在分子、细胞和组织水平上了解炎症和细胞死亡通路之间的相互作用。*我们的具体目标是了解在体外调节炎性小体活动的详细生化过程(目标1)。我们将评估XIAP在体内炎症小体活动和下垂中的作用(目标2)。我们将评估提高RPE中XIAP水平的策略，以进一步探讨XIAP在体外和体内调节年龄相关炎症体活动的能力(目标3)。*这些目标设计了一个重要的培训部分，使我们能够优先考虑所有级别的学生的公平参与，为未来在加拿大的学术界和工业界就业提供HQP。提出的研究计划很重要；它将促进我们对体内平衡细胞功能以及炎症和细胞死亡之间关系的基本理解。预期的结果包括在RPE和视网膜的分子、细胞和组织水平上对炎症、上睑下垂和细胞凋亡的调控途径的新发现。这些结果将被用于更广泛的应用和未来的研究，如细胞应激反应、免疫调节、细胞死亡途径以及大脑和眼睛的衰老。

***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.