Elucidating the molecular and cellular functions of polyamines

项目总结 多胺是具有两个或两个以上胺基的小有机化合物。这些进化上的古老生物 代谢物是各种细胞过程所必需的，包括细胞的生长和存活。 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，并且 多胺水平的变化扰乱了许多细胞过程，包括DNA压缩、转录、 翻译、自噬和压力反应。多胺代谢的中断也在几个 疾病。多胺代谢途径的基因突变与Snyder的学习障碍有关- 罗宾逊综合征，是帕金森氏症的已知危险因素。在许多人中，多胺水平升高 癌症，并有巨大的兴趣将这一途径作为化疗的靶点。从机械上讲， 多胺代谢的中断如何影响细胞功能并导致疾病尚不清楚。精准的 细胞中多胺的生化功能仍然是个谜。我们知识上的这种鸿沟源于内在 探测多胺的技术困难。 这个项目将提供新的方法和概念框架来阐明分子功能 多胺。首先，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动态平衡，并确定相关的蛋白质 在他们的领悟中。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， 还有翻译。通过交付新技术和功能框架，这项工作将推进我们的 了解多胺在细胞中的作用，可能有助于解开这些物质的药理潜力 保健和治疗疾病中的代谢物。

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.