Neutral sphingomyelinases and bioactive ceramides

中性鞘磷脂酶和生物活性神经酰胺

• 批准号: 9071506
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 70.92万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071506
• 关键词: Cell Cycle Checkpoint; Cell Nucleus; Cell membrane; Cells; Cellular Stress; Ceramides; DNA; DNA Damage; Data; Enzymes; Goals; Individual; Light; Lipids; Mediating; Metabolism; Nuclear; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phosphoric Monoester Hydrolases; Process; Regulation; Research Proposals; Role; Solid; Sphingolipids; Sphingomyelinase; Stimulus; Structure; Transducers; Work; Yeasts; base; biological adaptation to stress; place fields; public health relevance; response

 DESCRIPTION (provided by applicant): The overall goals of this research proposal are to define specific pathways of sphingolipid metabolism, define specific roles, define mechanisms, and help place the field of bioactive lipids on solid mechanistic grounds. Based on strong ongoing data, we propose the overall hypothesis that individual enzymes of ceramide metabolism serve as transducers of specific inputs, and the product bioactive sphingolipids function to mediate key responses. This proposal will develop this paradigm in the case of the DNA damage response and other stimuli activating neutral sphingomyelinases in distinct compartments leading to formation of ceramide which acts primarily in a cell cycle checkpoint. We propose the following specific goals: 1. What are the mechanisms involved in induction of nSMase2 and Isc1? 2. How are nSMase2 and Isc1 activated in the nucleus? Is there a specific role for nuclear PIP2? 3. Define mechanisms of regulation and the structure of neutral sphingomyelinases 4. What is the structure of lipids in the nucleus? 5. What is the specific function of nSMase2 (and Isc1) in checkpoints? 6. Do nuclear phosphatases mediate the action of nuclear ceramide; what are the mechanisms involved? 7. Define parallel pathways of bioactive sphingolipids in yeast. Taken together, we endeavor to advance our understanding of bioactive sphingolipids and reduce its complexities to manageable and specific components that promise to shed important light on how these specific pathways function, and their specific roles in stress responses. The ongoing results are defining a totally unexpected role for neutral sphingomyelinases in the eukaryotic DNA damage response through a nuclear lipid-mediated pathway.

 描述（由申请人提供）：本研究提案的总体目标是定义鞘脂代谢的特定途径，定义特定的作用，定义机制，并帮助将生物活性脂质领域置于坚实的机制基础上。基于强有力的持续数据，我们提出总体假设，即神经酰胺代谢的单个酶充当特定输入的转导器，并且产物生物活性鞘脂起到介导关键反应的作用。该提案将在 DNA 损伤反应和其他刺激激活不同区室中的中性鞘磷脂酶的情况下开发这种范例，从而导致主要在细胞周期检查点起作用的神经酰胺的形成。我们提出以下具体目标： 1. nSMase2 和 Isc1 的诱导涉及哪些机制？ 2. nSMase2和Isc1如何在细胞核中被激活？核 PIP2 是否有特定作用？ 3. 定义中性鞘磷脂酶的调节机制和结构 4. 细胞核中脂质的结构是什么？ 5. nSMase2（和Isc1）在检查点中的具体功能是什么？ 6. 核磷酸酶是否介导核神经酰胺的作用？涉及哪些机制？ 7. 定义酵母中生物活性鞘脂的平行途径。总而言之，我们努力增进对生物活性鞘脂的理解，并将其复杂性降低为可管理的特定成分，这些成分有望为了解这些特定途径的功能及其在应激反应中的特定作用提供重要线索。正在进行的结果明确了中性鞘磷脂酶通过核脂质介导的途径在真核 DNA 损伤反应中发挥着完全意想不到的作用。