Neutral Sphingomyelinases and Bioactive Ceramides

中性鞘磷脂酶和生物活性神经酰胺

• 批准号: 10437811
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 73.6万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437811
• 关键词: Cell Nucleus; Cell membrane; Cellular Stress; Ceramides; DNA Damage; Data; Enzymes; Foundations; Goals; Health; Individual; Light; Lipids; Malignant Neoplasms; Mediating; Metabolism; Nuclear; Pathway interactions; Process; Protein phosphatase; Regulation; Research Personnel; Research Proposals; Role; Solid; Sphingolipids; Sphingomyelinase; Stimulus; Structure; Therapeutic; Transducers; Work; Yeasts; base; biological adaptation to stress; enzyme pathway; human disease; place fields; response; tool

Abstract 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 mammalian and yeast neutral sphingomyelinases in distinct compartments leading to formation of compartmentalized and species-specific ceramides. We propose the following major goals: 1. Advance our understanding of structure and activation of nSMase2; 2. Develop tools and approaches to probe compartment-specific functions of bioactive sphingolipids and neutral sphingomyelinases; 3. Define functions and mechanisms of neutral sphingomyelinases in the nucleus, especially in the DNA Damage Response; and 4. Define mechanisms of regulation of protein phosphatases by ceramides. Taken together, we endeavor to advance our understanding of bioactive sphingolipids and reduce the complexities of the field 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 totally unexpected roles for neutral sphingomyelinases in distinct compartments, including the eukaryotic DNA damage response through a nuclear lipid-mediated pathway. These are critical towards the understanding of human disease (cancer) and therapeutics.

抽象的 该研究建议的总体目标是定义鞘脂代谢的特定途径， 定义特定角色，定义机制并帮助将生物活性脂质的领域放在固体机械上 理由。基于强大的持续数据，我们提出了一个总体假设，即 神经酰胺代谢是特定输入的换能器，产物生物活性鞘脂功能 调解关键反应。在DNA损伤响应的情况下，该提案将发展此范式 以及其他刺激激活不同隔室中的哺乳动物和酵母中性鞘磷脂素酶 形成分隔和物种特异性神经酰胺。我们提出以下主要目标：1。 促进我们对NSMase2的结构和激活的理解； 2。开发工具和方法 探测生物活性鞘脂和中性鞘磷脂酶的特异性功能； 3。 定义核中中性鞘磷脂素酶的功能和机制，尤其是在DNA中 伤害响应；和4。定义神经酰胺调节蛋白质磷酸酶的机制。拍摄 我们一起努力提高我们对生物活性鞘脂的理解，并减少 易于管理和特定组成部分的领域，有望为这些特定的特定方式提供重要的启示 途径功能及其在压力反应中的特定作用。正在进行的结果完全定义 中性鞘磷脂素酶在不同隔室中的意外作用，包括真核DNA 通过核脂质介导的途径的损伤反应。这些对于理解 人类疾病（癌症）和治疗学。