Autophagy regulation of apoptosis and necroptosis within cell populations

自噬对细胞群内凋亡和坏死性凋亡的调节

• 批准号: 10417174
• 负责人: James V Degregori
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417174
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; BBC3 gene; BCL2L11 gene; BH3 Domain; Binding Sites; Cell Death; Cells; Cessation of life; Clinical; Clinical Trials; Complex; Cytotoxic agent; Dose; Drug resistance; Evolution; Exposure to; FOXO3A gene; Funding; Future; Genes; Genetic; Gold; Grant; Heterogeneity; Human Genome; Introns; Malignant Neoplasms; Methods; Molecular; Mutation; Necrosis; Outer Mitochondrial Membrane; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Population; Process; Proteins; RIPK3 gene; Recycling; Regulation; Reporting; Resistance; Signal Transduction; Stimulus; TP53 gene; Techniques; Tertiary Protein Structure; Testing; Variant; Work; base; cancer cell; cancer therapy; cell type; improved; inhibitor; insight; intervention effect; neoplastic cell; novel; novel strategies; optogenetics; outcome prediction; response; scaffold; side effect; therapy resistant; transcription factor; treatment response; tumor heterogeneity

An important unsolved question in cell death is to understand why different cells within a population vary in their responses. Which cells will live or die and what determines exactly how they die after exposure to a death stimulus? These questions underlie fundamental cell fate decisions and also have important practical ramifications, for example, during cancer therapy when non-heritable, heterogeneous responses to anti-cancer drugs underlie the eventual acquisition of resistance to therapy. Heterogeneity in cell responses can be driven by stable genetic differences between cells, which are easy to understand. However, such differences also occur even in genetically homogeneous cell populations. What underlies these differences? More important, can we manipulate these effects? Previous work supported by this grant discovered that even in a homogeneous population of cells under unstressed conditions, there is extensive variation in the amount of autophagic flux, which in turn predicts the outcome to future treatment with a death stimulus. And, in the last funding period, we discovered a specific mechanism by which autophagy controls the apoptosis threshold and a quite different mechanism by which the autophagy machinery can control necroptosis. Building on these previous studies, we hypothesize: autophagy controls apoptotic and necroptotic thresholds by regulating Mitochondrial Outer Membrane Permeabilization (MOMP). And, this explains cell death variation between cells in a population. We will test this hypothesis by completing the following aims using a variety of new approaches including the first method that allows optogenetic regulation of autophagy. Specific Aim 1. Test if autophagy variation before and after a death stimulus controls heterogeneity in apoptosis responses in a cell population. Specific Aim 2. Determine how autophagy regulates necroptosis. By completing these aims, we will gain new insights into the interplay between two major forms of programmed cell death (apoptosis and necroptosis) and uncover how autophagy regulates these processes.

在细胞死亡中一个重要的悬而未决的问题是理解为什么一个群体中不同的细胞在 他们的反应。哪些细胞会存活或死亡，以及是什么决定了它们在暴露于 死亡刺激？这些问题是基本细胞命运决定的基础，也具有重要的现实意义 例如，在癌症治疗期间，当对抗癌的非遗传性、异质性反应时 药物是最终对治疗产生抵抗力的基础。细胞反应的异质性可以被驱动 通过细胞之间稳定的遗传差异，这是很容易理解的。然而，这样的差异也 即使在遗传上相同的细胞群体中也会发生。这些差异背后的原因是什么？更重要的是， 我们能操纵这些影响吗？这笔赠款支持的以前的工作发现，即使在 在非应激条件下，细胞的数量有广泛的差异 自噬通量，这反过来又预测了未来的治疗结果与死亡刺激。在最后一次， 期间，我们发现了一种特定的机制，通过自噬控制细胞凋亡阈值和 自噬机制可以控制坏死性下垂的一个完全不同的机制。建立在这些基础上 在之前的研究中，我们假设：自噬通过调节 线粒体外膜通透性(MOMP)这解释了细胞之间的死亡差异 在一群人中。我们将通过使用各种新的 方法包括第一种允许光基因调控自噬的方法。具体目标1.测试是否 死亡刺激前后的自噬变化控制细胞中凋亡反应的异质性 人口。具体目标2。确定自噬如何调节坏死性下垂。通过实现这些目标，我们 将获得对两种主要形式的程序性细胞死亡(细胞凋亡和细胞死亡)之间相互作用的新见解 坏死性下垂)，并揭示自噬如何调节这些过程。