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

基本信息

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
项目类别：
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

项目摘要

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.

该项目是由β细胞周期循环周期进入β细胞的底座的前提，这将为恢复细胞质量和糖尿病的功能提供潜力。急性重新恢复细胞复制。）利用聚酰胺在EIF5A上进行组合。 β细胞的生长和复制。以相关的专业知识，新的有条件敲除小鼠的定位，并将mRNA翻译工具归为这一假设。与LL一样的功能。因此，在β细胞的殖民地序言中的作用明智之举。