Mechanisms of Regulated Cell Death

调节细胞死亡的机制

• 批准号: 9756352
• 负责人: DOUGLAS R GREEN
• 金额: $ 104.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9756352
• 关键词: Apoptosis; Apoptotic; Area; Arithmetic; BCL2 gene; Caspase; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Childhood; Databases; Equation; Family; Future; Genome; Goals; Laboratories; Life; Malignant Neoplasms; Mitochondria; Molecular; Necrosis; Pathology; Pathway interactions; Patient-Focused Outcomes; Process; Proteins; Regulation; Research; Resistance; Saint Jude Children' s Research Hospital; Stimulus; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Work; Xenograft Model; base; programs; success; tool

A simple arithmetic of life is this: if cells in a tissue divide more frequently than they die, the tissue grows; if cells die more frequently than they divide, the tissue shrinks. This basic principle is enshrined as a “hallmark” of cancer—for a cancer to exist it must evade cell death mechanisms that would shift this equation to attrition. For three decades my laboratory has worked to understand the core pathways of regulated cell death and how they are controlled at the molecular level. This program of research, the continuation of which is proposed in this application, explores the processes of regulated cell death in the forms of apoptosis and necroptosis, and seeks to understand how they are tied to other cellular physiologies, as they must be. Three general goals of this research are outlined as questions, as follows. A. What are the mechanisms of cell survival in apoptosis/necroptosis and how do these integrate with cell life? Here we use the concept of “persisters,” cells that survive the activation of core apoptotic or necroptotic pathways, to probe the pathways that, when engaged, restrict these core pathways to enable transient resistance to the stimulus. We prioritize our “hits” based on those whose expression correlates with patient outcome in cancer databases, including the TCGA and St. Jude Pediatric Genome Project. These are tested in cancer xenograft models. B. How do diverse processes of cellular life integrate with the core mechanisms of apoptosis? The mitochondrial pathway of apoptosis is generally known to depend on the activation of the Bcl-2 family effectors, Bax and Bak by BH3- only proteins. We will continue to explore alternative mechanisms of mitochondrial permeabilization and how they are regulated by components of the cellular physiology. Prioritization and testing is as above. C. How do diverse processes of cellular life integrate with the mechanisms of necroptosis? Necroptosis is a form of regulated necrosis that is actively inhibited by the action of a caspase, normally associated with apoptosis (but here with cell survival). We will continue our studies into the activation and regulation of necroptosis in relation to cellular physiology and develop tools to probe its activation in the context of cancer and other pathologies. While the understanding of the core pathways of cell death have led to one approved cancer therapeutic, our continued “life and death” efforts set the stage for future success in this critical arena.

生命的一个简单算术是：如果组织中的细胞比死亡更频繁地分裂，则组织会生长； 细胞死亡的频率比分裂的频率更高，组织收缩。这个基本原则被视为“标志” 癌症的存在 - 为了存在癌症，必须逃避将该方程式转移到损耗的细胞死亡机制。 三十年来，我的实验室一直致力于了解受调节细胞死亡的核心途径以及如何 它们在分子水平上受到控制。这个研究计划，该计划的延续是在 该应用探讨了细胞凋亡和坏死形式的调节细胞死亡过程，以及 试图了解它们如何与其他细胞生理学联系在一起。三个总目标 这项研究被概述为问题，如下所示。答：细胞存活的机制是什么 凋亡/坏死性凋亡以及这些如何与细胞寿命整合在一起？在这里，我们使用“ persisters”，细胞的概念 在核心凋亡或坏死途径的激活中幸存下来，以探测当途径时 参与，限制了这些核心途径，使其能够对刺激的短暂抗性。我们优先考虑“命中” 基于那些与癌症数据库中患者结局相关的表达的人，包括TCGA 和圣裘德小儿基因组项目。这些在癌症特征模型中进行了测试。 B.潜水员如何 与凋亡的核心机制相结合的细胞寿命过程？线粒体途径 通常已知凋亡取决于BH3-的Bcl-2家族效应，BAX和BAK的激活 只有蛋白质。我们将继续探索线粒体通透性的替代机制以及如何 它们受细胞生理的成分调节。优先级和测试如上所述。 C.怎么做 细胞寿命整合与坏死性机制的各种过程？坏死性是 caspase的作用积极抑制了受调节的坏死，通常与凋亡有关（但是 在这里具有细胞存活）。我们将继续研究关系的激活和调节 在癌症和其他病理的背景下探测其激活的工具。 虽然对细胞死亡核心途径的理解导致一种批准的癌症治疗，但我们 持续的“生与死”努力为在这个关键领域的未来成功奠定了基础。