Hypusine as a nutrient-sensing modulator of eIF5A function in β cells

Hypusine 作为 β 细胞中 eIF5A 功能的营养感应调节剂

• 批准号: 10679499
• 负责人: Cara Anderson
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679499
• 关键词: Acute; American; Amino Acids; Animal Model; Animals; Arginine; Beta Cell; Biology; Blindness; Cause of Death; Cell Line; Cell Proliferation; Cell division; Cell physiology; Cells; Chemicals; Chicago; Chronic; Clinical; Data; Data Analyses; Diabetes Mellitus; Diagnosis; Disease; Disparity; EIF-2alpha; Enzymes; Exhibits; Fatty acid glycerol esters; Fostering; Future; Genes; Health; Heart Diseases; Homeostasis; Homologous Gene; Impairment; In Vitro; Insulin; Insulin Resistance; Investigation; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Lead; Life; Literature; Macronutrients Nutrition; Manuscripts; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Modification; Molecular; Mus; Nutrient; Nutritional Study; PRKR gene; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Polyamines; Prediabetes syndrome; Prevalence; Principal Investigator; Process; Production; Proliferating; Protein Isoforms; Proteins; Public Health; Publications; Putrescine; Regulation; Research; Research Personnel; Risk; Role; Science; Signal Transduction; Spermidine; Spermine; Stimulus; Structure of beta Cell of islet; Therapeutic; Time; Training; Transcript; Transfection; Transfer RNA; Translational Regulation; Translational Repression; Translations; United States; Universities; Writing; biological adaptation to stress; career development; cell type; comorbidity; deoxyhypusine synthase; detection of nutrient; doctoral student; eIF-5A; experimental study; feeding; glucose tolerance; hypusine; in vitro Model; in vivo; in vivo Model; inhibitor; insulin secretion; islet; knock-down; limb amputation; mRNA Translation; meetings; mouse model; pre-doctoral; programs; response; skills; small hairpin RNA; transcription factor; translation factor; type I and type II diabetes; virtual

PROJECT SUMMARY: This application is a proposal to train a predoctoral student with a passion for studying nutritional regulation of metabolic disease. I will conduct research in the laboratory of Dr. R. Mirmira at the University of Chicago and will engage in career development activities to foster my aim to lead an academic research program as a principal investigator. Career development activities will include formal training in the art of scientific writing, opportunities for presentation at regional and national meetings, and writing opportunities that include manuscripts for publication. The majority of time will be spent in primary research at the bench involving studies related to diabetes, an increasingly prevalent threat to public health in the United States. The research program will focus on the biology of the islet β cell, which is known to be defective in virtually all forms of diabetes. Understanding the stimuli and mechanisms of endogenous β cell mass expansion has powerful therapeutic potential, and the proposal will study a rare and unusual modification known as hypusination. Deoxyhypusine synthase (DHPS) catalyzes the formation of the rare amino acid hypusine on eIF5A, activating its known function as a translation factor. DHPS deficiency in the β cell results in mice that exhibit impaired β cell adaptive proliferation, emphasizing the role for this unusual modification in normal β cell responses. However, deletion of DHPS in this model also increases the prevalence of un-hypusinated eIF5A (eIF5ALys), and it remains unknown if the phenotype observed might emanate from the presence of this form as opposed to the absence of the hypusinated form of the factor (eIF5AHyp). My preliminary data indicate an interaction between eIF5ALys and the kinase Gcn2, which phosphorylates and inhibits the translation factor eIF2-α during amino acid scarcity. Association between Gcn2 and eIF5ALys suggests a possible role in negative translation regulation and nutrient homeostasis for this uncharacterized isoform. I hypothesize that eIF5ALys functions as a negative regulator of mRNA translation and its accumulation in the islet β cell suppresses adaptive β cell proliferation. To investigate this hypothesis, I will achieve the following two specific aims: (1) Investigate the metabolic effects of eIF5ALys accumulation in β cells in vivo, and (2) Define the molecular mechanisms governing eIF5ALys regulation of protein translation in β cells. This proposal will target a gap of knowledge in the literature regarding the unmodified form of eIF5A and elaborate on the therapeutic potential of modulating the hypusination for β cell proliferation in diabetes. Completing these studies will reinforce skills in data interpretation, research independence, and project management in me as a young investigator so that I can make future independent and impactful contributions to science.

项目概要： 这个应用程序是一个建议，培养一个博士前的学生与研究营养的热情 调节代谢疾病。我将在R博士的实验室进行研究。米尔米拉大学 芝加哥，并将从事职业发展活动，以培养我的目标，领导一个学术研究 作为首席研究员。职业发展活动将包括艺术方面的正式培训， 科学写作，在区域和国家会议上发言的机会，以及 包括供出版手稿。大部分时间将花在板凳上的主要研究 涉及与糖尿病相关的研究，糖尿病是美国日益普遍的公共健康威胁。的 研究计划将集中在胰岛β细胞的生物学上，众所周知，几乎所有形式的胰岛β细胞都有缺陷 糖尿病了解内源性β细胞团扩增的刺激和机制具有强大的 该提案将研究一种罕见而不寻常的修饰，称为hypusination。 脱氧羟腐胺赖氨酸合酶（DHPS）催化eIF 5A上稀有氨基酸羟腐胺赖氨酸的形成， 它的已知功能是翻译因子。β细胞中DHPS缺乏导致小鼠表现出受损的β 细胞适应性增殖，强调这种不寻常的修饰在正常β细胞反应中的作用。 然而，在该模型中DHPS的缺失也增加了未羟腐胺赖氨酸化的eIF 5A（eIF 5ALys）的患病率， 目前尚不清楚观察到的表型是否可能源于这种形式的存在， 缺乏羟腐胺赖氨酸化形式的因子（eIF 5AHyp）。我的初步数据显示 在eIF 5ALys和激酶Gcn 2之间，Gcn 2磷酸化并抑制翻译因子eIF 2-α， 氨基酸缺乏Gcn 2和eIF 5ALys之间的关联表明在负翻译中可能起作用 调节和营养稳态的这种未表征的异构体。我假设eIF 5ALys的功能是 mRNA翻译的负调节因子及其在胰岛β细胞中的积累抑制适应性β细胞 增殖为了研究这一假设，我将实现以下两个具体目标：（1）研究 eIF 5ALys在体内β细胞中积累的代谢效应，以及（2）定义分子机制 控制eIF 5ALys对β细胞中蛋白质翻译的调节。该提案将针对以下方面的知识空白： 关于未修饰形式的eIF 5A的文献，并详细阐述了调节eIF 5A的治疗潜力。 羟腐胺赖氨酸对糖尿病β细胞增殖的影响完成这些研究将加强数据技能 解释，研究独立性和项目管理在我作为一个年轻的研究者，使我可以 为科学做出独立和有影响力的贡献。