Mechanisms of Regulated Cell Death

调节细胞死亡的机制

• 批准号: 10229410
• 负责人: DOUGLAS R GREEN
• 金额: $ 107.7万
• 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/10229410
• 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.

一个关于生命的简单算术是这样的：如果组织中的细胞分裂比死亡更频繁，组织就会生长；如果 细胞死亡比分裂更频繁，组织收缩。这一基本原则被奉为“标志”。 癌症--为了癌症的存在，它必须避开细胞死亡机制，而细胞死亡机制会将这个等式转变为消耗。 三十年来，我的实验室一直致力于了解调控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。这项研究计划的延续是#年提出的。 这项应用探索了以细胞凋亡和坏死性下垂的形式调节细胞死亡的过程，以及 试图了解它们是如何与其他细胞生理联系在一起的，因为它们肯定是。的三个总体目标 这项研究被概括为以下问题。A.细胞存活的机制是什么？ 细胞凋亡/坏死性下垂及其与细胞生命的关系？在这里，我们使用“持久者”的概念，细胞 在核心的凋亡或坏死性通路激活后存活下来，以探索当 参与，限制这些核心通路，以实现对刺激的瞬时抵抗。我们优先考虑我们的“热门话题” 基于癌症数据库中那些其表达与患者预后相关的基因，包括TCGA 和圣犹大儿科基因组计划。这些都在癌症异种移植模型中进行了测试。B.如何实现多样化 细胞生命过程与细胞凋亡的核心机制相结合？线粒体途径的研究 众所周知，细胞凋亡依赖于BH3-BH3激活Bc l-2家族效应物Bax和Bak。 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 它们受细胞生理学成分的调节。优先级排序和测试如上所述。C.怎么做？ 细胞生命的不同过程与坏死性下垂的机制相结合？坏死性下垂是一种 受调节的坏死，被caspase的作用主动抑制，通常与细胞凋亡有关(但 这里与细胞存活有关)。我们将继续研究坏死性下垂的激活和调节机制。 到细胞生理学，并开发工具，以探索其在癌症和其他病理背景下的激活。 虽然对细胞死亡的核心途径的了解已经导致了一种被批准的癌症治疗方法，但我们的 持续的“生死”努力为未来在这一关键领域取得成功奠定了基础。