CAREER: Metabolic Determinants of Programmed Cell Death in Hepatic Lipotoxicity

职业：肝脂毒性中程序性细胞死亡的代谢决定因素

• 批准号: 0955251
• 负责人: Jamey Young
• 金额: $ 40万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0955251&HistoricalAwards=false
• 关键词: CAREER; Metabolic; Determinants; Programmed; Cell

0955251YoungThe overall objective of the current application is to elucidate the mechanism by which metabolic changes activate apoptotic signaling in hepatic cells exposed to elevated saturated fatty acids (SFAs).The central hypothesis is that endoplasmic reticulum (ER) stress induced by SFAs leads to altered coupling between central carbon pathways, which subsequently triggers mitochondrial accumulation of reactive oxygen species (ROS) resulting in apoptosis. The rationale for the proposed research is that, once it is known how metabolic pathway fluxes impact lipid-induced apoptosis, these pathways can be modulated by therapeutic interventions that target the underlying metabolic factors causing lipotoxicity. The plan is to test the central hypothesis by pursuing the following specific aims. First, to determine the mechanism by which SFAs induce ROS accumulation in hepatic cells. Second, to identify the lipid intermediate responsible for inducing ER stress in SFA-treated hepatic cells. These aims will be accomplished using a systems approach that focuses on integrated metabolic pathways versus individual reactions and where the concept of the metabolic network is of central importance. The approach involves both GC-MS metabolic profiling to track the relative concentrations and isotopic labeling patterns of many different intracellular metabolites simultaneously, as well as metabolic flux analysis (MFA) to reconstruct comprehensive flux maps that represent the dynamic flow of material throughout the network. By subjecting hepatic cells to a variety of treatments aimed at perturbing lipid and central carbon metabolism, they will dissect the pathways involved in SFA-induced lipotoxicity.

0955251Young当前申请的总体目标是阐明代谢变化激活暴露于升高的饱和脂肪酸（SFA）的肝细胞中的凋亡信号传导的机制。中心假设是SFAs诱导的内质网（ER）应激导致中央碳途径之间的耦合改变，从而触发线粒体 活性氧（ROS）的积累导致细胞凋亡。这项研究的基本原理是，一旦了解代谢途径通量如何影响脂质诱导的细胞凋亡，就可以通过针对引起脂毒性的潜在代谢因素的治疗干预措施来调节这些途径。该计划是通过追求以下具体目标来检验中心假设。首先，确定 SFA 诱导肝细胞中 ROS 积累的机制。其次，鉴定负责在 SFA 处理的肝细胞中诱导 ER 应激的脂质中间体。这些目标将通过系统方法来实现，该方法侧重于综合代谢途径与个体反应，其中代谢网络的概念至关重要。该方法涉及 GC-MS 代谢分析，以同时跟踪许多不同细胞内代谢物的相对浓度和同位素标记模式，以及代谢通量分析 (MFA)，以重建代表整个网络中物质动态流动的综合通量图。通过对肝细胞进行各种旨在扰乱脂质和中心碳代谢的治疗，他们将剖析参与 SFA 诱导的脂毒性的途径。