Understanding how exocrine-derived signals promote beta cell growth

了解外分泌信号如何促进 β 细胞生长

基本信息

批准号：
10750765
负责人：
Danielle Louisia Overton
金额：
$ 3.88万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2024
资助国家：
美国
起止时间：
2024-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750765
关键词：
Ablation Acinar Cell Adult Advisory Committees Age Anabolism Area Award Beta Cell Biology Cell Differentiation process Cell Proliferation Cell physiology Cells Communication Data Diabetes Mellitus Diet Disease Embryo Endocrine Enzymes Eukaryotic Initiation Factors Exocrine pancreas Exocrine pancreatic insufficiency Functional disorder Funding Genes Genetic Growth Health Homeostasis Hormone secretion Impairment Incidence Indiana Individual Insulin Islets of Langerhans Life Mass Spectrum Analysis Measures Mediating Mentors Metabolic Metabolic Diseases Molecular Mus Oral Pancreas Pancreatitis Pathway interactions Peptide Initiation Factors Phenocopy Play Post-Translational Protein Processing Process Proliferating Protein Biosynthesis Protein Secretion Proteins Proteomics Publishing Research Research Personnel Resources Role Signal Transduction Sucrose Techniques Testing Tissues Training Translations United States National Institutes of Health Universities Work Writing body system career development cell growth comparative deoxyhypusine synthase differential expression eIF-5A experimental study hypusine mRNA Translation medical schools mouse model mutant novel pancreas development postnatal skills therapeutic development

项目摘要

PROJECT SUMMARY The pancreas has commonly been considered two distinct organ systems wherein the endocrine compartment is responsible for hormone secretion and the exocrine compartment is responsible for the secretion of digestive enzymes. Although distinct, the endocrine and exocrine pancreas are functionally and structurally connected, working together to maintain metabolic homeostasis. Diseases of the exocrine can impact the endocrine; however, not all cases of exocrine disease result in endocrine dysfunction. For example, 50 - 80% of individuals with pancreatitis or exocrine insufficiency do not develop diabetes. This suggests that in certain instances the loss of exocrine pancreas may support the continued growth and function of the endocrine. Currently, there remains an incomplete understanding of the molecular pathways and communications that exist between cells of the endocrine and exocrine pancreas. Published studies and preliminary data from our lab reveal that hypusine biosynthesis plays a role in exocrine growth and function, which in turn may influence beta cell growth. Hypusine biosynthesis involves the post-translational modification of eukaryotic translation initiation factor 5A (eIF5A) by the enzyme deoxyhypusine synthase (DHPS) to form hypusinated eIF5A (eIF5AHyp), which functions in mRNA translation. Our studies demonstrate that loss of eIF5A in the developing pancreas causes a reduction in the synthesis of proteins involved in exocrine growth and function as well a loss of exocrine mass. Interestingly, the reduction in exocrine mass is concomitant with an increase in beta cell mass. Therefore, I hypothesize that the loss of exocrine mass, rather than altered mRNA translation, at the stage of exocrine differentiation drives beta cell growth due to the reduced amount of exocrine and exocrine- derived proteins. To test this hypothesis and determine if it is the loss of exocrine or the loss of eIF5A that stimulates beta cell expansion, I will perform experiments outline in two specific aims. Experiments in aim 1 will investigate how the absence of exocrine instructs beta cell growth in the embryonic and adult setting. Experiments in aim 2 will investigate how alterations in mRNA translation directly impacts exocrine growth and, resultantly, beta cell mass. In particular, my studies may identify exocrine-derived factors stimulate beta cell growth. Moreover, this award will provide critical holistic training encompassing five central objectives, which include: 1) building a strong background in techniques and concepts pertinent to diabetes research; 2) honing my scientific writing skills communication; 3) practicing my oral scientific communication; 4) enhancing my skills as a mentor; and 5) professional career development. My training plan also includes direct and enthusiastic support from my sponsor and co-sponsor, a thesis advisory committee composed of established NIH-funded investigators, and all of the resources/facilities in the IUPUI Department of Biology and the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine, which will help me progress in my path to become an independent, diabetes-focused researcher.

项目概要胰腺通常被认为是两个不同的器官系统，其中内分泌室负责激素的分泌，外分泌室负责消化液的分泌酶。内分泌胰腺和外分泌胰腺虽然不同，但在功能和结构上是相关的，共同努力维持代谢稳态。外分泌疾病会影响内分泌；然而，并非所有外分泌疾病都会导致内分泌功能障碍。例如，50 - 80% 患有胰腺炎或外分泌功能不全的人不会患上糖尿病。这表明在某些情况下在某些情况下，外分泌胰腺的丧失可能支持内分泌的持续生长和功能。目前，对分子途径和通讯的了解仍然不完全。存在于内分泌和外分泌胰腺细胞之间。我们已发表的研究和初步数据实验室揭示，高尿苷生物合成在外分泌生长和功能中发挥作用，进而可能影响 β细胞生长。木叶碱生物合成涉及真核翻译的翻译后修饰起始因子 5A (eIF5A) 通过脱氧马尿苷合成酶 (DHPS) 形成马尿苷化 eIF5A (eIF5AHyp)，在 mRNA 翻译中发挥作用。我们的研究表明，发育中的 eIF5A 缺失胰腺会导致参与外分泌生长和功能的蛋白质合成减少以及外分泌质量损失。有趣的是，外分泌质量的减少伴随着β细胞的增加大量的。因此，我推测外分泌质量的损失，而不是 mRNA 翻译的改变，在外分泌分化阶段由于外分泌和外分泌数量减少而驱动β细胞生长衍生蛋白质。为了检验这一假设并确定是外分泌的缺失还是 eIF5A 的缺失导致了刺激 β 细胞扩增，我将按照两个具体目标进行实验概述。目标 1 中的实验将研究外分泌的缺失如何指导胚胎和成人环境中的 β 细胞生长。目标 2 中的实验将研究 mRNA 翻译的改变如何直接影响外分泌生长，结果，β细胞团。特别是，我的研究可能会确定外分泌源性因子刺激β细胞生长。此外，该奖项将提供包含五个中心目标的关键整体培训，其中包括：1）建立与糖尿病研究相关的技术和概念的强大背景； 2）珩磨我的科学写作技巧沟通； 3）练习口语科学交流； 4）增强我的作为导师的技能； 5) 职业生涯发展。我的训练计划还包括直接和来自我的赞助商和共同赞助商的热情支持，论文咨询委员会由已成立的 NIH 资助的研究人员以及 IUPUI 生物学系和中心的所有资源/设施印第安纳大学医学院的糖尿病和代谢疾病专业，这将帮助我取得进步在我成为一名独立的、专注于糖尿病的研究员的道路上。