Caspases in Inflammatory Cell Death Networks

项目总结 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 这个话题对疾病和治疗有积极和消极的影响，如果我们要理解 病理结果和治疗益处我们需要更好地了解哪里的机制 炎症源于。制定这项建议的大局是为了了解 炎症，因为它们与调节细胞死亡有关。这项申请寻求大幅推进电流 深入研究细胞死亡和炎症后果的方法、概念和技术 细胞死亡机制之间的联系。我们结合了生物化学，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，以探索相互关联的促和抗 炎性细胞死亡机制。我们提出了一种稳健和量化的方法来定义 炎症是这项提议的一个重要创新特征。这项建议的主要目标是1) 计算因细胞凋亡、下垂和坏死性下垂而释放的炎症介质的差异 在巨噬细胞中，2)确定炎症细胞死亡过程中细胞释放细胞因子的机制， 3)了解半胱氨酸氨基转移酶在上睑下垂中的激活机制，合成高选择性的半胱氨酸氨基转移酶 荧光探针，允许直接显示特定的caspase激活。

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.