Caspases in Inflammatory Cell Death Networks

项目摘要 慢性炎症是癌症、糖尿病和神经变性的主要原因。炎症是一种复杂的 主题，对疾病和治疗都有积极和消极的影响，如果我们要了解 病理结果和治疗益处，我们需要更好地了解 炎症起源。这一建议的大背景是了解 炎症，因为它们与受调节的细胞死亡有关。本申请寻求实质上提高电流 方法，概念和技术，深入研究细胞死亡的炎症后果， 细胞死亡机制之间的联系我们结合了联合收割机生物化学，细胞生物学，基因组编辑， 炎症，蛋白质工程和化学生物学的非动物模型，以探索相关的亲和抗- 炎症细胞死亡机制。我们建议，一个强大的和定量的方法来定义 煽动性是这一提议的一个重要创新性质。该提案的主要目标是：（1） 计算由于细胞凋亡、细胞凋亡和细胞坏死而释放的炎症介质的差异 在巨噬细胞中，2）确定了从经历炎性细胞死亡的细胞释放细胞因子的机制， 了解caspase在细胞凋亡中的激活机制， 荧光探针以允许特异性胱天蛋白酶活化的直接可视化。

PROJECT SUMMARY Chronic inflammation is a major cause of cancer, diabetes, and neurodegeneration. Inflammation is a complex topic, with both positive and negative effects on disease and therapy, and if we are to understand the pathological results and therapeutic benefits we need to better understand the mechanisms of where inflammation originates. The big picture in which this proposal is set is to understand the mechanisms of inflammation as they relate to regulated cell death. This application seeks to substantially advance current approaches, concepts, and technology to delve deeply into the inflammatory consequences of cell death and the connections between the cell death mechanisms. We combine biochemistry, cell biology, genome editing, non-animal models of inflammation, protein engineering, and chemical biology to explore linked pro- and anti- inflammatory cell death mechanisms. We propose that a robust and quantitative approach to defining inflammation is an important innovative quality of this proposal. The main goals of this proposal are to 1) compute the difference in inflammatory mediators released as a result of apoptosis, pyroptosis and necroptosis in macrophages, 2) define the mechanism of cytokine release from cells undergoing inflammatory cell death, and 3) understand the activation mechanisms of caspases in pyroptosis, and synthesize highly selective fluorescent probes to allow for direct visualization of specific caspase activation.