Role of Polyamines and Hypusine in Nutrient-Induced Beta-Cell Growth and Replication

多胺和马尿苷在营养诱导的 β 细胞生长和复制中的作用

• 批准号: 10613949
• 负责人: Laura C Alonso
• 金额: $ 56.67万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-07 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613949
• 关键词: ATF6 gene; Acute; Amino Acids; Anabolism; Arginine; Assessment tool; Beta Cell; Biogenic Amines; Biosensor; Cell Cycle; Cell Proliferation; Cells; Cellular biology; Cessation of life; Collection; Data; Dependence; Diabetes Mellitus; Diet; Disease; Enzymes; Functional disorder; Gatekeeping; Genetic; Genetic Transcription; Glucose; Glutamine; Growth; Growth and Development function; Human; Hyperglycemia; Image; Insulin; Knockout Mice; Leucine; Link; Mediating; Messenger RNA; Metabolic; Methionine; Modeling; Modification; Molecular; Mus; Natural regeneration; Nutrient; Nutritional; Obesity; Ornithine Decarboxylase; Pathway interactions; Phase; Phenylalanine; Polyamines; Positioning Attribute; Production; Proliferating; Proline; Proteins; Publishing; Reagent; Ribosomes; Rodent; Role; Signal Induction; Signal Transduction; Spermidine; Stress; Techniques; Technology; Testing; Time; Translations; blood glucose regulation; cell growth; conditional knockout; deoxyhypusine synthase; eIF-5A; experimental study; functional restoration; hypusine; in vivo; islet; mRNA Translation; mouse model; novel; obesogenic; response; small molecule; transcription factor; translation factor; virtual

This project is inspired by the premise that signals and substrates extrinsic to the β-cell trigger cell cycle entry, and that reactivation of the cell cycle in β-cells would provide the potential for restoring β-cell mass and function in diabetes. Our published and preliminary data suggest that the translation factor eIF5A functions as an acute response factor that catalyzes translation of specific mRNAs, enabling cellular replication. Strikingly, eIF5A is the only protein containing the unique, polyamine-derived amino acid hypusine, which is required for its function. Hypusine formation occurs posttranslationally and is governed by two rate-limiting enzymes, ornithine decarboxylase (ODC) and deoxyhypusine synthase (DHPS). ODC generates intracellular polyamines from arginine (and indirectly from glutamine, proline, methionine, phenylalanine, leucine), and DHPS utilizes the polyamine spermidine to form hypusine on eIF5A. Collectively, we refer to the ODC/DHPS/eIF5A proteins as belonging to the “polyamine/hypusine pathway.” Because polyamine and hypusine productions can be manipulated by diet and/or small molecules, they represent real-world targets to intervene in β-cell growth and replication. We hypothesize that the pathway that generates polyamines and hypusine links nutritional signals (amino acids, glucose) to mRNA translation to enable adaptive β-cell replication. The strength of this Multi-PI R01 application is the collaborative effort between Drs. R. Mirmira (an expert in the polyamine/hypusine pathway in β-cells) and L. Alonso (an expert in β-cell replication); our Team is uniquely positioned with the relevant expertise, novel conditional knockout mice, and mRNA translation assessment tools to test this hypothesis. We propose the following 3 aims: Aim 1: Elucidate the mechanisms by which the polyamine/hypusine pathway governs adaptive β-cell proliferation in models of obesity and hyperglycemia. Aim 2: Characterize how polyamine biosynthesis functions as a nutrient-activated gatekeeper for the proliferative signal induced by the UPR in β-cells. Aim 3: Reveal an unusual function of eIF5A as a biosensor for amino acid and polyamine supply. We will use a comprehensive toolbox of state-of-the-art imaging and cell biology techniques and novel reagents, including the only collection of ODC/DHPS/eIF5A knockout mice, to reveal a role in β-cell proliferation for an otherwise enigmatic pathway. Therefore, the primary impact of this proposal is the identification and mechanisms of the polyamine/hypusine pathway in rodent and human β-cell replication.

该项目的灵感来自于β细胞触发细胞周期进入的信号和底物的前提，并且β细胞中细胞周期的重新激活将为恢复型β细胞质量和糖尿病的功能提供潜力。我们发表的初步数据表明，翻译因子EIF5A是催化特定mRNA翻译的急性响应因子，从而实现了细胞复制。引人注目的是，EIF5A是唯一包含独特的多胺氨基酸降压素的蛋白质，这是其功能所需的。非素形成发生后翻译，并由两种限速酶，鸟氨酸脱羧酶（ODC）和脱氧蛋白酶合酶（DHP）控制。 ODC从精氨酸（并间接地从谷氨酰胺，脯氨酸，甲基丙氨酸，亮氨酸）产生细胞内聚胺，而DHPS利用多胺精子素在EIF5A上形成了多胺。总的来说，我们将ODC/DHPS/EIF5A蛋白称为“多胺/非肌途径”。由于可以通过饮食和/或小分子来操纵多胺和非素生产，因此它们代表了现实世界中的靶标，以干预β细胞的生长和复制。我们假设产生多胺和非沿体的途径将营养信号（氨基酸，葡萄糖）连接到mRNA转换以实现自适应β细胞复制。此多PI R01应用程序的优势是DR之间的协作努力。 R. Mirmira（β细胞中多胺/非肌途径的专家）和L. alonso（β细胞复制专家）；我们的团队以相关的专业知识，新颖的有条件敲除小鼠和mRNA翻译评估工具的独特位置来检验这一假设。我们提出了以下3个目标：目标1：阐明多胺/非肌途径在肥胖和高血糖模型中控制自适应β细胞增殖的机制。 AIM 2：表征多胺生物合成如何充当β细胞中UPR诱导的增殖信号的营养激活的网守。 AIM 3：揭示EIF5A作为氨基酸和多胺供应的生物传感器的异常功能。我们将使用最先进的成像和细胞生物学技术和新型试剂的全面工具箱，包括唯一的ODC/DHPS/EIF5A敲除小鼠的收集，以揭示在其他神秘途径中的作用。因此，该提案的主要影响是啮齿动物和人β细胞复制中多胺/非肌途径的鉴定和机制。

项目成果

SARS-CoV-2 infection of islet β cells: Evidence and implications.

• DOI: 10.1016/j.xcrm.2021.100380
• 发表时间: 2021-08-17
• 期刊: Cell reports. Medicine
• 作者: Clark AL;Mirmira RG
• 通讯作者: Mirmira RG