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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.

细胞整合营养感知和代谢来协调适当的细胞反应