The role of autophagy in the escape from replicative crisis and tumorigenesis

自噬在逃避复制危机和肿瘤发生中的作用

基本信息

批准号：
10040400
负责人：
Joe Nassour
金额：
$ 16.31万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040400
关键词：
Autophagocytosis Award Binding Bioinformatics Biological Markers Bypass CDKN2A gene CRISPR screen CRISPR/Cas technology Cancer Biology Cell Aging Cell Cycle Arrest Cell Cycle Checkpoint Cell Death Cells Computer Analysis DNA Data Defect Development Double Minutes Educational process of instructing Excision Fluorescent in Situ Hybridization Frequencies Functional disorder Genes Genome Stability Genomics Grant Human Incidence Individual Knock-out Knockout Mice Knowledge Laboratories Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Measures Membrane Mentors Mentorship Methods Molecular Monitor Mouse Strains Mus Neoplastic Cell Transformation Oncogenic Pathway interactions Phase Play Precipitation Predisposition Premalignant Cell Prevention Proteins Proteomics Research Research Project Grants Risk Role Signal Pathway Stimulator of Interferon Genes TP53 gene Technology Telomere Shortening Testing Therapeutic Tissues Training Training Activity Transgenic Mice Tumor Suppressor Proteins Work Writing base cancer therapy carcinogenesis chromothripsis design epigenomics expectation genome sequencing genome-wide in vivo insight live cell imaging mouse model next generation sequencing novel receptor recruit response restraint senescence skills success telomere transcriptomics tumor tumorigenesis whole genome

项目摘要

Project Summary / Abstract Tumorigenesis requires cells to bypass or escape two discrete and distinctive anti-proliferative barriers: replicative senescence and crisis. Senescence is a permanent cell cycle arrest, activated as a primary response to telomere deprotection and involves stimulation of the tumor suppressor pathways p53-p21WAF1 and/or p16INK4A- Rb. Disruption of cell-cycle checkpoints renders cells capable of bypassing senescence and continuing proliferation, while telomeres shorten further. Eventually such cells initiate a terminal response called replicative crisis, during which critically short telomeres become subject to end-to-end fusions, resulting in massive cell death. On rare occasion, a small group of cells will emerge spontaneously from crisis and evolve towards malignancy, yet the mechanisms underlying cell death in crisis and crisis escape are not defined. Dr. Joe Nassour has recently discovered an unrecognized function for macroautophagy (hereafter autophagy) in the elimination of cells during crisis. Autophagy is therefore an essential component of the crisis response required for the removal of cells at risk for malignant transformation. This suggests that autophagy defects can be the molecular basis for tumorigenesis. In his Pathway to Independence Award (K99/R00) proposal, Dr. Nassour, together with his Mentor Dr. Jan Karlseder, and his Co-Mentors Dr. Reuben Shaw, Dr. Martin Hetzer, and Dr. Peter Adams, designed a dedicated training plan and proposed a research project that sets out to dissect the molecular basis of mammalian autophagy and its potential therapeutic role in the earliest stages of human cancer. In particular, Dr. Nassour will focus on deciphering the mechanism of autophagy-dependent cell death in crisis (Aim 1), elucidating the interplay between autophagy and genome stability (Aim 2), and evaluating the role of autophagy in neoplastic transformation through crisis escape (Aim 3). The in vivo relevance of Aim 3 will be examined by employing knockout and transgenic mouse models susceptible to telomere dysfunction-driven carcinogenesis. The occurrence of cellular crisis in tissues and the impact of autophagy on tumor incidence will be examined. This research will provide new insights into the function of autophagy in cancer biology, and should provide a rationale for developing autophagy modulation approaches to ameliorate the efficacy of cancer therapy. Dr. Nassour’s training plan will provide all the necessary professional development to direct an independent laboratory using next-generation sequencing (NGS)-based ‘omics’ approaches and transgenic mouse models to define the mechanisms and function of autophagy in cancer. Training modules in this award include: Computational analysis and bioinformatics for NGS data, methods for handling and restraint in the mouse, transgenic mouse technology, and mentorship skills such as teaching and grant writing; which will all be necessary for the success following the transition to independence.

项目概要/摘要肿瘤发生需要细胞绕过或逃避两个离散且独特的抗增殖屏障：复制性衰老和危机是一种永久性的细胞周期停滞，作为主要反应被激活。端粒去保护并涉及肿瘤抑制途径 p53-p21WAF1 和/或 p16INK4A- 的刺激 Rb. 细胞周期检查点的破坏使细胞能够绕过衰老并继续衰老增殖，而端粒进一步缩短，最终这些细胞启动称为复制的终端反应。危机，在此期间极短的端粒发生端到端融合，导致大量细胞在极少数情况下，一小群细胞会自发地摆脱危机并进化到死亡。恶性肿瘤，但危机中细胞死亡和危机逃避的机制尚未明确。最近发现了宏自噬（以下简称自噬）在消除过程中的一个未被识别的功能因此，细胞自噬是危机应对的重要组成部分。去除有恶性转化风险的细胞，这表明自噬缺陷可能是分子机制。肿瘤发生的基础。 Nassour 博士和他的导师 Jan 博士在他的独立之路奖 (K99/R00) 提案中 Karlseder 和他的合作导师 Reuben Shaw 博士、Martin Hetzer 博士和 Peter Adams 博士设计了一个专门的培训计划并提出了一个研究项目，旨在剖析哺乳动物的分子基础 Nassour 博士特别介绍了自噬及其在人类癌症早期阶段的潜在治疗作用。重点破译危机中自噬依赖性细胞死亡的机制（目标1），阐明自噬与基因组稳定性之间的相互作用（目标 2），并评估自噬在肿瘤中的作用通过危机逃避进行转型（目标 3）将通过采用来检验目标 3 的体内相关性。敲除和转基因小鼠模型易受端粒功能障碍驱动的致癌作用。将检查组织中细胞危机的发生以及自噬对肿瘤发生率的影响。研究将为自噬在癌症生物学中的功能提供新的见解，并应提供一个基本原理开发自噬调节方法以提高癌症治疗的功效。纳苏尔博士的培训计划将提供所有必要的专业发展，以指导独立的实验室使用基于下一代测序（NGS）的“组学”方法和转基因小鼠模型来定义癌症中自噬的机制和功能。该奖项的培训模块包括： NGS 数据的计算分析和生物信息学、小鼠的处理和约束方法、转基因小鼠技术以及教学和资助写作等指导技能；独立过渡后取得成功所必需的。