Molecular and Cellular Mechanisms of Copper-Dependent Nutrient Signaling and Metabolism

铜依赖性营养信号传导和代谢的分子和细胞机制

• 批准号: 10406688
• 负责人: Donita C Brady
• 金额: $ 48.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406688
• 关键词: Amino Acids; Applications Grants; Area; Autophagocytosis; Binding; Biogenesis; Biology; Carbohydrates; Cell Death; Cell Proliferation; Cell physiology; Copper; Development; Disease; Ensure; Enzymes; Equilibrium; Event; Homeostasis; Knowledge; Life; Lipids; MAP2K1 gene; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Molecular; Nutrient; Oxidation-Reduction; Oxygen; Phenotype; Phosphotransferases; Physiological; Physiology; Protein Kinase; Proteins; Recycling; Regulation; Research; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Therapeutic; Transition Elements; clinically relevant; cofactor; detection of nutrient; dietary; energy balance; flexibility; lipid metabolism; novel; phosphoric diester hydrolase; therapeutic target

Molecular and Cellular Mechanisms of Copper-Dependent Nutrient Signaling and Metabolism PROJECT SUMMARY/ABSTRACT Akin to organic nutrients, such as oxygen, lipids, amino acids, and carbohydrates, the transition metal copper (Cu) is an essential dietary nutrient for normal physiology and development. Decades of research highlight the physiological and disease associated consequences of disrupting homeostatic mechanisms that ensure proper Cu acquisition, storage, and distribution to Cu-dependent enzymes. However, phenotypes associated with alterations in Cu availability cannot be fully explained by the limited number of enzymes that traditionally harness the redox potential of Cu as a catalytic cofactor. Recent discoveries in Cu biology have revealed direct Cu binding at non-catalytic sites within signaling molecules that modulate cell proliferation via the protein kinases MEK1/2, lipid metabolism via the phosphodiesterase PDE3B, and nutrient recycling via the autophagic kinases ULK1/2. The emergence of this new paradigm in nutrient sensing and protein regulation has established that Cu is a critical mediator of intracellular signaling, provided evidence for the existence of molecular mechanisms for sensing changes in Cu abundance, and expanded the contribution of Cu to cellular processes necessary for adaptation to nutrient scarcity. This grant proposal will focus on the intersections between Cu homeostasis, nutrient signaling, and metabolism by examining the interplay between mechanisms of Cu-sensing necessary for cellular energy homeostasis and evaluating the necessity of Cu for metabolic flexibility under nutrient and oxygen stress. Specifically, we will build on our novel findings from the past 5 years by elucidating mechanisms of: i) Cu-controlled autophagy-lysosomal biogenesis and function, ii) Cu-mediated metabolic flexibility via direct control of glycolytic flux, and iii) interconnectivity between mitochondrial Cu transport and cytosolic nutrient sensing signaling pathways necessary for metabolism. By launching these three interconnected focus areas, we will increase our fundamental knowledge of the molecular and cellular features of Cu-dependent enzymes and cellular processes and enable therapeutic targeting of Cu-dependent disease vulnerabilities.

铜依赖性营养信号传导和代谢的分子和细胞机制 项目概要/摘要 类似于有机营养素，如氧、脂质、氨基酸和碳水化合物，过渡金属铜 (Cu) 是正常生理和发育必需的膳食营养素。数十年的研究强调 破坏确保适当的稳态机制的生理和疾病相关后果 Cu 的获取、储存和分配给 Cu 依赖性酶。然而，与相关的表型 传统上利用的酶数量有限，无法完全解释铜利用率的变化 Cu 作为催化辅助因子的氧化还原电位。铜生物学的最新发现揭示了铜的直接结合 在通过蛋白激酶 MEK1/2 调节细胞增殖的信号分子内的非催化位点， 通过磷酸二酯酶 PDE3B 进行脂质代谢，通过自噬激酶 ULK1/2 进行营养物回收。 这种营养传感和蛋白质调节新范式的出现证实了铜是一种 细胞内信号传导的关键介质，为分子机制的存在提供了证据 感测铜丰度的变化，并扩大铜对细胞过程所需的贡献 适应营养缺乏。该拨款提案将重点关注铜稳态之间的交叉点， 通过检查必要的铜感应机制之间的相互作用来研究营养信号和代谢 用于细胞能量稳态并评估铜在营养和营养条件下代谢灵活性的必要性 氧应激。具体来说，我们将在过去 5 年的新发现的基础上阐明机制 i) Cu 控制的自噬溶酶体生物发生和功能，ii) Cu 通过直接介导的代谢灵活性 糖酵解通量的控制，以及 iii) 线粒体铜转运和胞质营养物之间的互连性 传感新陈代谢所需的信号通路。通过启动这三个相互关联的重点领域，我们 将增加我们对铜依赖性酶的分子和细胞特征的基础知识 和细胞过程，并能够针对铜依赖性疾病的脆弱性进行治疗。