Admin Supplement: Neutral Sphingomyelinases and Bioactive Ceramides

摘要 本研究提案的总体目标是确定鞘脂代谢的特定途径， 定义具体作用，定义机制，并帮助将生物活性脂质领域置于坚实的机制之上 场.基于强有力的正在进行的数据，我们提出了总体假设，即 神经酰胺代谢作为特异性输入的转换器，其产物具有生物活性的鞘脂功能 来调节关键反应。这项建议将在DNA损伤反应的情况下发展这种范式 和其它刺激物在不同的区室中激活哺乳动物和酵母中性鞘磷脂酶， 形成区室化和物种特异性的神经酰胺。我们提出以下主要目标：1. 推进我们对nSMase 2的结构和激活的理解; 2.开发工具和方法 探索生物活性鞘脂和中性鞘磷脂酶的区室特异性功能; 3. 定义中性鞘磷脂酶在细胞核，尤其是DNA中的功能和机制 损害赔偿; 4。定义神经酰胺调节蛋白磷酸酶的机制。采取 我们共同奋进，以提高我们的生物活性鞘脂的理解和减少的复杂性， 领域的可管理和具体的组成部分，承诺阐明这些具体的 途径的功能，以及它们在应激反应中的具体作用。持续的结果完全定义了 中性鞘磷脂酶在包括真核DNA在内的不同区室中的意外作用 通过核脂质介导的途径损伤反应。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.