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

经典抗凋亡蛋白 XIAP 对炎症小体活性的调节。

• 批准号: RGPIN-2018-04996
• 负责人: Matsubara, Joanne
• 金额: $ 7.29万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761871
• 关键词: Regulation; inflammasome; activity; classic; anti

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.

在一生中，我们体内的组织经历复杂的稳态控制，以实现细胞死亡和生存机制之间的平衡，这对于在成年动物中不复制的终末分化、有丝分裂后细胞（例如大脑和视网膜中的神经元）尤其重要。我们对视网膜色素上皮 (RPE)（一种单层有丝分裂后细胞）的研究表明，在衰老过程中，稳态机制会恶化，RPE 会屈服于细胞应激。免疫系统的特殊臂炎体存在并保护 RPE 免受细胞应激。然而，由于未知的原因，在衰老过程中，炎性体失调和过度活跃导致慢性炎症，最终导致 RPE 细胞凋亡和焦亡。两条候选细胞死亡途径影响衰老的 RPE 细胞凋亡是一种程序性死亡途径，被称为“礼貌细胞死亡”，因为细胞会缓慢收缩并死亡，而不会干扰附近的细胞。细胞焦亡是另一种类型的程序性死亡，或“细胞火死”，其中细胞膨胀、破裂和死亡，对附近组织造成灾难性影响。我们最近对 RPE 的研究表明，X 染色体的蛋白质水平相关。细胞凋亡抑制剂（XIAP，一种关键的细胞凋亡抑制剂）和炎症小体活性（焦亡的关键指标）呈负相关，这种独特的负相关关系表明细胞凋亡和炎症小体活性之间存在负相关。焦亡途径在蛋白质水平上相互作用并相互调节。我的研究计划的长期目标是了解衰老视网膜中分子、细胞和组织水平上炎症和细胞死亡途径之间的相互作用。了解调节体外炎症小体活性的详细生化过程（目标 1） 我们将评估 XIAP 在体内炎症小体活性和细胞焦亡中的作用（目标 2）。 RPE 中的 XIAP 水平，以进一步探讨 XIAP 在体外和体内调节与年龄相关的炎性体活动的能力（目标 3）。目标的设计包含重要的培训内容，以便我们优先考虑所有级别学生的公平参与，为加拿大学术界和工业界的未来就业提供 HQP 非常重要；它将促进我们对稳态细胞功能以及炎症与细胞死亡之间关系的基本了解。 RPE 和视网膜的分子、细胞和组织水平上的炎症、细胞焦亡和凋亡途径这些结果将用于细胞应激反应、免疫调节、细胞死亡途径和大脑衰老的更广泛应用和未来研究。和眼睛。