Exocrine-Endocrine Crosstalk and Determinants of Beta Cell Growth

外分泌-内分泌交叉和β细胞生长的决定因素

基本信息

批准号：
10153773
负责人：
Teresa Louise Mastracci
金额：
$ 38.36万
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：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10153773
关键词：
Ablation Acinar Cell Adult Affect Alleles Amino Acids Anabolism Area Beta Cell Biology Blood Glucose Cell Proliferation Cell Therapy Cell physiology Cells Cellular Stress Cre driver Cystic Fibrosis Data Development Diabetes Mellitus Diabetic mouse Diet Digestion Diphtheria Toxin Disease Drug Targeting Embryo Endocrine Enzyme Inhibitor Drugs Enzymes Eukaryotic Initiation Factors Exocrine pancreas Functional disorder Genes Genetic Translation Goals Growth Hormones Human Incidence Individual Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Knockout Mice Link Lysine Mass Spectrum Analysis Messenger RNA Metabolic Metabolic dysfunction Metabolism Modeling Molecular Mus Natural regeneration Organ Outcome Pancreas Pancreatic Diseases Pancreatic enzyme Pathway interactions Play Post-Translational Protein Processing Protein Biosynthesis Proteins Publishing Reporting Research Role Signal Transduction Structure Tamoxifen Testing Tissues Translations Weaning Work base cell growth cell regeneration chronic pancreatitis deoxyhypusine synthase enzyme deficiency human tissue hypusine in vivo interest islet islet stem cells mouse model mutant mutant mouse model novel pancreas development postnatal preservation prevent regenerative therapy therapeutic development tool translation factor

项目摘要

Destruction of insulin-producing beta cells in the pancreatic islets of Langerhans is central to the development of many forms of diabetes. As a result of beta cell loss, the body is unable to produce or respond to insulin, which leads to elevated blood glucose and abnormal metabolism. One potential approach to reverse the disease is to generate a therapy that specifically stimulates beta cell growth, thereby regenerating the lost cells and resolving metabolic dysfunction. My group is focused on understanding how the embryonic pancreas develops, with the goal to identify molecular pathways or specific factors that drive the expansion of beta cell mass. Specifically, current studies in the lab are investigating eukaryotic initiation factor 5A (eIF5A) and the hypusine biosynthesis pathway. eIF5A is a mRNA translation factor previously reported to play a role in cell proliferation but whose biology, to date, is relatively unexplored in pancreas development and beta cell regeneration. eIF5A is activated by the post-translational modification (“hypusination”) of a specific lysine residue by the enzyme deoxyhypusine synthase (DHPS). The active (hypusinated) form of eIF5A has been linked to postnatal beta cell stress. Moreover, a type 1 diabetes mouse model treated with a drug that targets the hypusination of eIF5A showed reduced incidence of diabetes. We recently made the discovery that hypusine biosynthesis is required for pancreas development. In particular, the absence of hypusine biosynthesis in the pancreas results in loss of pancreatic acinar (exocrine) cells. However, despite this dramatic loss of exocrine, there is actually an expansion of beta cell area and preserved islet function. From this preliminary work, we identified three fundamental, unanswered questions for our proposed studies: First, how does hypusine biosynthesis function to stimulate the expansion of beta cell mass? Second, are the signals that drive the beta cell growth emanating from exocrine cells? Third, can we exploit this mechanism to specifically regenerate the beta cells lost in individuals with diabetes? These questions will be answered in vivo and ex vivo, using both mouse and human-based tools. The proposed studies will define the interplay of exocrine and endocrine cell development and will identify novel targets that stimulate human beta cell growth.

胰岛中产生胰岛素的 β 细胞的破坏是多种糖尿病发生的核心。由于 β 细胞的损失，身体无法产生胰岛素或对胰岛素做出反应，从而导致血糖升高和糖尿病。逆转这种疾病的一种潜在方法是开发一种专门刺激β细胞生长的疗法，从而再生丢失的细胞并解决代谢功能障碍。途径具体来说，实验室目前的研究正在研究真核起始因子 5A (eIF5A) 和前叶嘧啶生物合成途径，eIF5A 是一种 mRNA 翻译因子，之前报道在细胞增殖中发挥作用。迄今为止，其生物学在胰腺发育和 β 细胞再生中相对未被探索。 eIF5A 的活性（hypusinated）形式与出生后 β 细胞应激有关。此外，用针对 eIF5A hypusination 的药物治疗的 1 型糖尿病小鼠模型显示，eIF5A 的发生率降低。我们最近发现，胰腺的发育需要高尿嘧啶生物合成，特别是胰腺中缺乏高尿嘧啶生物合成。导致胰腺腺泡（外分泌）细胞损失。然而，尽管外分泌细胞大量损失，但β细胞面积实际上有所扩大，并且胰岛功能得以保留。从这项初步工作中，我们确定了我们提出的研究中三个尚未解答的基本问题。：第一，高尿苷生物合成如何刺激β细胞团的扩张？第二，驱动β细胞生长的信号是否来自外分泌细胞？第三，我们可以利用这种机制来特异性再生吗？糖尿病患者中β细胞的丢失？这些问题将通过小鼠和人体工具在体内和体外得到解答。拟议的研究将确定外分泌和内分泌细胞发育的相互作用，并确定刺激人类的新靶标。 β细胞生长。