Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics

确定连接脂质信号传导和表观遗传学的亚细胞器

基本信息

批准号：
9763211
负责人：
Matthew D Hirschey
金额：
$ 21万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763211
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylation Adverse event Affect Animals Applications Grants Biological Models CRISPR screen Candidate Disease Gene Caprylates Carbon Catabolism Cell Cycle Cell Cycle Inhibition Cell Line Cell Nucleus Cell Proliferation Cell model Cell physiology Cells Chromatin Citrates Cleaved cell Collaborations Communication Data Deposition Diet Dietary Intervention Disease Endoplasmic Reticulum Enzymes Epigenetic Process Event Fatty Acids Future Gene Activation Gene Expression Gene Expression Profile Generations Genes Glucose Glycolysis Goals Health Health Benefit Histone Acetylation Histones Human In Vitro Incidence Intelligence Knock-out Knowledge Lead Link Lipids Location Lysine Malignant Neoplasms Malignant neoplasm of liver Mediating Mediator of activation protein Medium chain triglycerides Metabolic Metabolism Mitochondria Molecular Monitor Nuclear Nutrient Organelles Outcome Oxides Pathway interactions Pharmacology Play Post-Translational Protein Processing Prevention therapy Production Protein Isoforms Proteins Public Health Publishing Recurrence Reporting Repression Role Serum Signal Transduction Site Source Starvation System Testing Therapeutic Tumor Burden Universities Wood material Work biological adaptation to stress cancer prevention cancer therapy cdc Genes detection of nutrient epidemiology study epigenome gene induction genetic approach glucose metabolism histone modification improved innovation lipid mediator lipid metabolism mouse model novel nutrient metabolism oxidation oxidized lipid peroxisome pre-clinical prevent programs response stable isotope therapy design treatment response treatment strategy

项目摘要

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part, by increasing glucose-derived histone acetylation. We recently expanded the known metabolites that integrate into epigenetic signaling and found that medium-chain lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. This signaling axis leads to activation of stress response genes, including lipid metabolic genes, and inhibition of cell cycle gene expression. Our preliminary data presented in this application expand upon these gene expression observations and reveal lipid oxidation induces potent suppression of the cell cycle, lowers cellular proliferation across a range of cell lines, and lowers tumor burden in a mouse model of liver cancer. However, a critical gap in our knowledge remains that prevent us from fully understanding how the role of lipids and their oxidation in cancer: In which sub-cellular organelle are medium-chain lipids oxidized to generate acetyl-CoA for histone acetylation? Is the oxidation of MCTs required for their effect on cellular proliferation? What are the key cellular mediators of these epigenetic signals? There is a critical need to understand the full range of lipid’s molecular effects in order to enable more intelligent therapies for cancer. Although it is widely accepted that mitochondria oxidize lipids and are prime candidate sites of mediating communication between nutrients and the nucleus, no data exist to support this notion. Therefore, the single objective of this exploratory grant application is to determine the site(s) and molecular mediators of lipid signaling on epigenetics. Aim 1 will test three candidate sites of lipid metabolism using a combination of pharmacological and genetic approaches. In a complementary parallel approach, Aim 2 will perform an unbiased CRISPR- Cas9 screen to identify genes that are required for the suppressive effects of medium-chain lipids on cellular proliferation. This project is significant because it will explain the molecular mechanisms by which lipids and their oxidation mediate the positive effects cellular proliferation and cancer outcomes. We put forth conceptual and technical innovations that will both follow directed hypotheses and allow unbiased discovery of the most important aspects of the response to medium-chain lipids. Successful completion of this project will identify new aspects of inter- organelle communication in cancer.

细胞整合营养感应和新陈代谢，以协调细胞对营养物质的适当反应例如，葡萄糖驱动特定的基因表达程序。通过激活参与其代谢的基因，部分是通过增加葡萄糖衍生的组蛋白我们最近扩展了整合到表观遗传信号中的已知代谢物。并发现中链脂质衍生的乙酰辅酶A是组蛋白的主要碳源该信号轴导致应激反应基因的激活，包括脂质。我们的初步数据显示在代谢基因和细胞周期基因表达的抑制中。该应用扩展了这些基因表达观察并揭示了脂质氧化诱导细胞周期的有效抑制，降低一系列细胞的细胞增殖线，并降低肝癌小鼠模型中的肿瘤负荷。然而，我们的研究存在重大差距。知识仍然阻碍我们充分理解脂质及其作用癌症中的氧化：亚细胞器中的中链脂质被氧化生成组蛋白乙酰化中的乙酰辅酶 A 是否需要 MCT 的氧化才能对细胞产生影响？这些表观遗传信号的关键细胞介质是什么？需要全面了解脂质的分子效应，以便实现更智能的尽管人们普遍认为线粒体氧化脂质是主要的治疗方法。介导营养物质和细胞核之间通讯的候选位点，没有数据表明因此，本次探索性拨款申请的唯一目标是目标 1 将测试表观遗传学中脂质信号传导的位点和分子介质。结合药理学和遗传的脂质代谢的三个候选位点在互补的并行方法中，Aim 2 将执行无偏见的 CRISPR- Cas9 筛选以确定中链脂质抑制作用所需的基因这个项目很重要，因为它将解释分子增殖。脂质及其氧化介导细胞增殖积极作用的机制我们提出了随之而来的概念和技术创新。定向假设并允许公正地发现响应的最重要方面该项目的成功完成将确定中间链脂质的新方面。癌症中的细胞器通讯。