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.

项目摘要： 该申请是一项提议，旨在培训一名热情学习营养的学生 代谢疾病的调节。我将在大学的R. Mirmira博士实验室进行研究 芝加哥并将从事职业发展活动，以促进我的目标 作为首席研究员的计划。职业发展活动将包括对艺术的正式培训 科学写作，区域和国家会议上的演讲机会以及写作机会 包括手稿出版。大部分时间将用于替补席的基础研究 涉及与糖尿病有关的研究，这是对美国公共卫生的日益普遍威胁。 研究计划将重点介绍胰岛β细胞的生物学，该细胞几乎在所有形式上都有缺陷 糖尿病。了解内源性β细胞质量膨胀的刺激和机制具有强大 治疗潜力，该提案将研究一种罕见且异常的修饰，称为非偶然性。 脱氧蛋白合酶（DHP）催化EIF5A上稀有氨基酸的降丁酸的形成，激活 它已知作为翻译因子的功能。 β细胞中的DHP缺乏导致暴露于β受损的小鼠中 细胞自适应增殖，强调了这种异常修饰在正常β细胞反应中的作用。 但是，在该模型中，DHP的删除还增加了未催化性EIF5A（EIF5ALYS）， 而且尚不清楚观察到的表型是否可能从这种形式的存在中散发出来 由于没有该因子的含量不足的形式（EIF5AHYP）。我的初步数据表明互动 在EIF5ALYS和激酶GCN2之间，它们磷酸化和抑制了翻译因子EIF2-α 氨基酸稀缺。 GCN2和EIF5ALYS之间的关联表明在负翻译中可能起作用 对这种未表征的同工型的调节和营养稳态。我假设eif5alys起作用 mRNA翻译的阴性调节剂及其在胰岛β细胞中的积累抑制适应性β细胞 增殖。为了调查这一假设，我将达到以下两个具体目标：（1）研究 EIF5ALYS在体内积累的代谢作用，（2）定义分子机制 β细胞中蛋白质翻译的eif5alys调节。该建议将针对知识差距 有关未修饰形式EIF5A的文献，并详细介绍了调节的治疗潜力 糖尿病中β细胞增殖的非胰腺。完成这些研究将增强数据的技能 我作为年轻的研究者的解释，研究独立性和项目管理，以便我可以 做出对科学的未来独立和有影响力的贡献。