Mechanisms of Regulated Cell Death

一个简单的生命算术是这样的：如果组织中的细胞分裂比死亡更频繁，组织就会生长; 细胞死亡的频率比分裂的频率高，组织就会萎缩。这一基本原则被奉为"标志"， 对于癌症的存在，它必须逃避细胞死亡机制，这将使这个等式变成消耗。 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，其中提出的继续在 本申请探索了以凋亡和坏死性凋亡形式的受调节的细胞死亡的过程， 试图了解它们是如何与其他细胞生理学联系在一起的，因为它们必须如此。三大目标 本研究以问题的形式概述如下。a.细胞存活的机制是什么？ 细胞凋亡/坏死性凋亡以及这些如何与细胞生命整合？这里我们使用"坚持者"的概念， 在核心凋亡或坏死性凋亡通路激活后存活下来，以探测当 参与，限制这些核心途径，使瞬态电阻的刺激。我们优先考虑我们的"命中" 基于那些表达与癌症数据库中患者结果相关的基因，包括TCGA 和圣裘德儿科基因组计划这些在癌症异种移植模型中进行了测试。B。如何做到多样化 细胞生命的过程与细胞凋亡的核心机制相结合？线粒体途径 细胞凋亡通常已知依赖于Bcl-2家族效应子Bax和巴克被BH 3- 只有蛋白质。我们将继续探索线粒体透化的替代机制，以及如何 它们受细胞生理学成分的调节。优先级和测试如上所述。C.怎么 细胞生命的不同过程与坏死性凋亡的机制相结合？坏死性上睑下垂是 受半胱天冬酶活性抑制的调节性坏死，通常与凋亡相关（但 这里是细胞存活）。我们将继续研究坏死性凋亡的激活和调节， 细胞生理学和开发工具来探测其在癌症和其他病理学背景下的激活。 虽然对细胞死亡核心途径的理解已经导致了一种批准的癌症治疗方法，但我们的研究表明， 持续的"生死"努力为今后在这一关键竞技场取得成功奠定了基础。

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.