Ceramide Synthases CERS5 and CERS6 Regulate Pathways of Programmed Cell Death

神经酰胺合成酶 CERS5 和 CERS6 调节程序性细胞死亡途径

• 批准号: 7660335
• 负责人: Thomas D Mullen
• 金额: $ 3.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2012-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660335
• 关键词: Adenocarcinoma Cell; Antioxidants; Apoptosis; Bax protein; Breast Adenocarcinoma; Cell Death; Cell Line; Cells; Ceramides; Cessation of life; Data; Disease; Enzymes; Generations; Genes; Genotoxic Stress; Goals; Health; Human; Investigation; Lipids; MCF7 cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Methodology; Mitochondria; Modeling; Morbidity - disease rate; Myocardial Ischemia; Organism; Pathway interactions; Play; Process; Production; Proteins; Regulation; Role; Sphingolipids; Stress; Stroke; System; Testing; Ultraviolet Rays; United States; cell growth; dihydroceramide; dihydroceramide desaturase; interest; killings; mortality; overexpression; oxidation; programs; repaired; response; therapeutic target

DESCRIPTION (provided by applicant): Humans, like all organisms, are subject to environmental stresses. To deal with these stresses, such as damage to the DMA or oxidation of proteins and lipids, our cells possess numerous protective mechanisms (e.g. DMA repair or anti-oxidant systems). However, when stresses become too great, our cells are programmed to kill themselves-a process called programmed cell death or apoptosis. Programmed cell death plays important roles in human health and disease; excessive programmed cell death leads to the significant morbidity and mortality associated with ischemic heart disease and stroke, whereas defective cell death leads to the second greatest cause of mortality in the United States, cancer. Sphingolipids are important regulators of cell growth and death. Ceramide, a bioactive sphingolipid, is an essential mediator of programmed cell death. Ceramide is produced by ceramide synthases (CerSes) during cell death, and there is an accumulating body of evidence that these enzymes play specific roles in regulating ceramide generation and cell death. However, the mechanisms of CerS- and ceramide-mediated cell death are ill-defined and warrant further study. By understanding the details of these pathways we will be able to identify targets of therapeutic interest. The goal of this project is to determine the role of CerSS and CerS6 in mediating programmed cell death. This project will utilize the MCF-7 breast adenocarcinoma cell line to investigate the contribution of CerSS and CerS6 to cell death induced by the genotoxic stress ultraviolet light (UVC). In preliminary investigations, the pro-death protein Bax has emerged as a downstream target of CerSS and CerS6- mediated ceramide production in UVC-induced death. The aims of this study are 1) determine how CerSS and CerS6 regulate cell death; 2) determine how CerSS and CerS6 are regulated during cell death; and 3) determine whether CerSS or CerS6-mediated ceramide production is sufficient to activate cell death pathways (e.g Bax). The primary methodology of these studies will be to overexpress or knockdown CerSS and CerS6 and examine subsequent effects on Bax activation and other parameters of cell death. This project represents an incremental step in achieving our long-term goal of determining the mechanisms of ceramide-mediated programmed cell death. Human cells respond to excessive stress by making a decision to kill themselves. This project seeks to determine how the lipid ceramide and the enzymes that make ceramide regulate this decision.

描述（由申请人提供）：与所有生物一样，人类受到环境压力的影响。为了处理这些应力，例如损害DMA或蛋白质和脂质的氧化，我们的细胞具有许多保护机制（例如DMA修复或抗氧化剂系统）。但是，当压力变得太大时，我们的细胞会被编程以杀死自己 - 一种称为编程细胞死亡或凋亡的过程。程序性细胞死亡在人类健康和疾病中起重要作用；过度编程的细胞死亡导致与缺血性心脏病和中风有关的显着发病率和死亡率，而有缺陷的细胞死亡导致了美国死亡率第二大原因，即癌症。鞘脂是细胞生长和死亡的重要调节剂。神经酰胺是一种生物活性鞘脂，是程序性细胞死亡的重要介质。神经酰胺是在细胞死亡期间由神经酰胺合酶（CERSE）产生的，并且有很多证据表明这些酶在调节神经酰胺的产生和细胞死亡方面起着特定的作用。但是，CERS和神经酰胺介导的细胞死亡的机制是不明的，需要进一步研究。通过了解这些途径的细节，我们将能够确定治疗兴趣的目标。该项目的目的是确定CERSS和CERS6在介导编程细胞死亡中的作用。该项目将利用MCF-7乳腺癌细胞系来研究CERSS和CERS6对遗传毒性应激紫外线（UVC）诱导的细胞死亡的贡献。在初步研究中，促血管蛋白BAX已成为CERSS和CERS6介导的神经酰胺在UVC诱导的死亡中的下游靶标。这项研究的目的是1）确定CERSS和CERS6如何调节细胞死亡； 2）确定在细胞死亡期间如何调节CERS和CERS6； 3）确定CERSS或CERS6介导的神经酰胺的产生是否足以激活细胞死亡途径（例如Bax）。这些研究的主要方法将是过表达或敲除CERSS和CERS6，并检查对BAX激活和细胞死亡其他参数的后续影响。该项目代表了确定神经酰胺介导的程序性细胞死亡机制的长期目标的增量步骤。人类细胞通过决定自杀而应对过度压力。该项目旨在确定使神经酰胺调节该决定的脂质神经酰胺和酶如何。