Admin Supplement: Neutral Sphingomyelinases and Bioactive Ceramides

摘要 这项研究计划的总体目标是确定鞘脂代谢的具体途径， 定义特定的角色，定义机制，并帮助将生物活性脂质领域放在固体机械上 地面。基于强劲的持续数据，我们提出了总体假设，即单个酶的 神经酰胺代谢作为特定输入的转导，产物具有生物活性的神经鞘脂起作用 来调停关键的反应。这一建议将在DNA损伤反应的情况下发展这一范例 和其他刺激激活哺乳动物和酵母中性鞘磷脂酶在不同的隔间导致 形成区域化的和物种特有的神经酰胺。我们提出了以下主要目标：1. 加深对nSMase2结构和激活的理解；2.开发工具和方法 探讨生物活性鞘磷脂和中性鞘磷脂酶的隔室特异性功能； 确定中性鞘磷脂酶在细胞核中的功能和机制，特别是在DNA中 确定神经酰胺调节蛋白磷酸酶的机制。已被占用 我们共同努力促进我们对生物活性鞘脂的理解，并降低 可管理的特定组件的领域，这些组件承诺为这些特定组件如何提供重要的说明 途径的功能，以及它们在应激反应中的具体作用。正在进行的结果完全定义了 中性鞘磷脂酶在不同的隔间中的意外作用，包括真核DNA 通过核脂介导的途径进行损伤反应。这些对于理解 人类疾病(癌症)和治疗学。

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.