Elucidating the molecular and cellular functions of polyamines

项目摘要 多胺是具有两个或更多个胺基的小有机化合物。这些进化上古老的 代谢物对于多种细胞过程是必需的，包括细胞生长和存活，并且存在于 在哺乳动物细胞中的毫摩尔浓度。细胞内多胺浓度受到严格控制， 多胺水平的变化破坏了许多细胞过程，包括DNA压缩，转录， 翻译、自噬和应激反应。多胺代谢的破坏也观察到在几个 疾病多胺代谢途径中的基因突变与Snyder的学习障碍有关- 罗宾逊综合征是帕金森病的已知危险因素。多胺水平升高， 癌症，并且对使用该途径作为化疗靶点存在巨大的兴趣。机械地说， 多胺代谢的破坏如何影响细胞功能并产生疾病尚不清楚。的精确 多胺在细胞中的生物化学功能仍然是个谜。我们知识上的这种差距源于内在的 探测多胺的技术困难。 该项目将提供新的方法和概念框架，以阐明 多胺第一，我们将开发新的定量分析方法来测量活细胞中的多胺浓度。 第二，我们将研究哺乳动物细胞如何维持多胺的稳态，并鉴定相关的蛋白质 在他们的吸收。第三，我们将研究细胞多胺水平的变化如何影响RNA的定位，结构， 和翻译。通过提供新技术和功能框架，这项工作将推动我们的 了解多胺在细胞中的作用，并可能有助于解锁这些药物的药理学潜力。 代谢物的健康和治疗疾病。

PROJECT SUMMARY Polyamines are small organic compounds with two or more amine groups. These evolutionarily ancient metabolites are essential for a variety of cellular processes, including cell growth and survival, and are present at milli-molar concentrations in mammalian cells. Cellular polyamine concentrations are tightly regulated, and changes in polyamine levels disrupt numerous cellular processes, including DNA compaction, transcription, translation, autophagy, and stress response. Disruption of polyamine metabolism is also observed in several diseases. Genetic mutations in polyamine metabolic pathways are linked with learning disability in Snyder- Robinson syndrome and are a known risk factor for Parkinson's disease. Polyamine levels are elevated in many cancers, and there is enormous interest in using this pathway as a chemotherapeutic target. Mechanistically, how disruption of polyamine metabolism affects cell function and produces disease is not known. The precise biochemical functions of polyamines in the cell remain mysterious. This gap in our knowledge stems from intrinsic technological difficulties in probing polyamines. This project will deliver new methods and conceptual frameworks to elucidate the molecular functions of polyamines. One, we will develop new quantitative assays to measure polyamine concentrations in living cells. Two, we will investigate how mammalian cells maintain polyamine homeostasis and identify the proteins involved in their uptake. Third, we will examine how changes in cellular polyamine levels affect RNA localization, structure, and translation. By delivering new technologies and functional frameworks, this work will advance our understanding of the roles of polyamines in the cell, and may help unlock the pharmacological potential of these metabolites in health and curing disease.