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这样的：如果组织中的细胞分裂次数多于死亡次数，则组织会生长； 细胞死亡的频率比分裂的频率高，组织会收缩，这一基本原理被奉为“标志”。 癌症的存在——癌症要存在，它必须逃避细胞死亡机制，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受调节的细胞死亡的核心途径以及如何 它们是在分子水平上进行控制的，该研究计划的延续已在 2017 年提出。 该应用探索了细胞凋亡和坏死性凋亡形式的受调节细胞死亡过程，以及 试图了解它们与其他细胞生理学的联系，因为它们必须如此。 这项研究被概述为问题，如下： A. 细胞存活的机制是什么。 细胞凋亡/坏死性凋亡以及它们如何与细胞生命结合？这里我们使用“细胞持续存在”的概念？ 在核心凋亡或坏死性途径的激活后存活下来，以探测当 参与，限制这些核心途径，以实现对刺激的短暂抵抗。我们优先考虑我们的“打击”。 基于癌症数据库（包括 TCGA）中表达与患者结果相关的那些 和圣裘德儿科基因组计划。这些都在癌症异种移植模型中进行了测试。 细胞生命过程与细胞凋亡的核心机制整合？ 通常已知细胞凋亡依赖于 BH3-Bcl-2 家族效应子 Bax 和 Bak 的激活 我们将继续探索线粒体透化的替代机制以及如何实现。 它们受细胞生理学组成部分的调节。优先级和测试如上所述。 细胞生命的不同过程与坏死性凋亡的机制相结合？ 受 caspase 作用主动抑制的调节性坏死，通常与细胞凋亡相关（但 我们将继续研究坏死性凋亡的激活和调节。 细胞生理学并开发工具来探测其在癌症和其他病理情况下的激活。 虽然对细胞死亡核心途径的理解已经导致一种被批准的癌症治疗方法，但我们的 持续的“生与死”努力为未来在这个关键领域的成功奠定了基础。