Arginine regulation of alpha cell proliferation and function

精氨酸调节α细胞增殖和功能

• 批准号: 10609909
• 负责人: Erika Danielle Dean
• 金额: $ 46.66万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609909
• 关键词: Acute; Affect; Affinity; Alpha Cell; Amino Acid Transporter; Amino Acids; Arginine; Award; Basic Amino Acid Transport Systems; Beta Cell; Binding; Binding Proteins; Blood; Blood Glucose; Blood specimen; Catabolism; Cations; Cell Proliferation; Cell Surface Proteins; Cell Surface Receptors; Cell membrane; Cell physiology; Cell secretion; Cell surface; Cells; Cellular biology; Complex; Data; Development; Diabetes Mellitus; Diet; Endocrine; Enzymes; Essential Amino Acids; Feedback; Fishes; Funding; Gene Expression; Gene Targeting; Glucagon; Glucagon Receptor; Gluconeogenesis; Glutamine; Goals; Hepatic; Human; Hyperglycemia; Hyperplasia; Impairment; Individual; Insulin; Interruption; Investigation; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kinetics; Knockout Mice; Leucine; Liver; Measures; Mediator; Membrane; Modeling; Molecular; Monitor; Mus; Names; Nature; Nutrient; Play; Proliferating; Proteins; Regulation; Role; Signal Transduction; Structure of alpha Cell of islet; Tertiary Protein Structure; Testing; Translating; Work; blood glucose regulation; extracellular; feeding; hepatic gluconeogenesis; hepatic ureagenesis; hyperglucagonemia; improved; insight; islet; live cell imaging; man; member; novel; novel therapeutic intervention; overexpression; pancreatic juice; protein expression; repaired; response; sensor; stem; targeted treatment; transcriptomics; type I and type II diabetes

PROJECT SUMMARY Traditionally, diabetes is defined as decreased insulin action resulting in impaired glucose homeostasis. However, inappropriate secretion of glucagon also contributes to the hyperglycemia in diabetes. Blocking glucagon action lowers blood glucose, but also leads to hyperglucagonemia with α cell proliferation and hyperplasia. We demonstrated that this is due to high blood levels of amino acids resulting from impaired amino acid catabolism in liver (gluconeogenesis). These studies demonstrated a classical endocrine feedback loop, the liver-islet α cell axis. As part of our K01 funded investigations, we discovered that high levels of arginine are required for the effects of high amino acid levels on α cell proliferation and function. We identified SLC7A2 (CAT2) is the major arginine transporter in pancreatic islet α cells. Using global CAT2 knockout mice, we found that loss of CAT2 results in protection from α cell hyperplasia and a complete loss of glucagon secretion even in response to strong depolarizing agents. This suggests that CAT2 is playing an important role in α cells beyond affecting membrane polarization as had been previously proposed as a mechanism for arginine-stimulated secretion. Our current objective is to define the mechanisms of arginine-stimulated α cell proliferation and secretion. Under the support of this R01 in Aim 1, we will characterize changes in the α cell when CAT2 expression is lost using α cell specific targeted deletion, including α cell proliferation and mass, glucagon secretion, Ca2+ dynamics, and gene and protein expression. We will also test if the heterodimeric amino acid exchanger LAT2 (SLC7A8/SLC3A2) is required for α cell proliferation and function. In Aim 2, we will examine a novel putative arginine cell surface binding protein called TM4SF4 that is selectively and robustly expressed on pancreatic α cells. We will fully characterize TM4SF4 arginine binding kinetics, protein binding partners in α cells, effects on arginine transport, and regulation of α cell proliferation and function. An important feature of our work is that we will translate our discoveries made in mouse islets using human islets. These studies will provide new insights into normal α cell function and how α cells could be targeted to repair dysregulated glucagon secretion in diabetes.

项目总结 传统上，糖尿病被定义为胰岛素作用减弱，导致葡萄糖稳态受损。 然而，不适当的胰升糖素分泌也是糖尿病高血糖的原因之一。阻止 胰高血糖素的作用降低血糖，但也会导致高血糖素血症与α细胞的增殖和 增生症。我们证明，这是由于血液中氨基酸水平较高所致 肝脏中的氨基酸分解代谢(糖异生)。这些研究证明了经典的内分泌反馈 环状，肝-胰岛α细胞轴。作为我们K01资助调查的一部分，我们发现高水平的 高水平的氨基酸对α细胞的增殖和功能的影响需要精氨酸。我们确认了 SLC7A2(CAT2)是胰岛α细胞的主要精氨酸转运体。使用全球CAT2基因敲除小鼠， 我们发现，CAT2的缺失导致了对α细胞增殖的保护和对胰升糖素的完全丧失 即使对强烈的去极剂有反应的分泌物。这表明CAT2在其中起着重要作用 在α细胞中，影响膜极化是先前提出的一种机制 精氨酸刺激的分泌。我们目前的目标是确定精氨酸刺激α细胞的机制 增殖和分泌。在AIM 1中此R01的支持下，我们将描述α细胞的变化 当使用α细胞特异性靶向缺失，包括α细胞增殖和质量时， 胰高血糖素分泌、钙动态、基因和蛋白表达。我们还将测试异二聚体是否 氨基酸交换器LAT2(SLC7A8/SLC3A2)是α细胞增殖和功能所必需的。在目标2中，我们 将检测一种新的推测的精氨酸细胞表面结合蛋白TM4SF4，它选择性地和 在胰腺α细胞上强势表达。我们将充分表征TM4SF4精氨酸结合动力学，蛋白质 α细胞中的结合伙伴，对精氨酸运输的影响，以及对α细胞增殖和功能的调节。一个 我们工作的一个重要特点是，我们将利用人类胰岛将我们在老鼠胰岛上的发现转化为人类胰岛。 这些研究将为正常的α细胞功能以及α细胞如何被靶向修复提供新的见解 糖尿病患者胰高血糖素分泌失调。