Arginine regulation of alpha cell proliferation and function

精氨酸调节α细胞增殖和功能

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要传统上，糖尿病被定义为胰岛素作用降低，导致葡萄糖稳态受损。然而，胰高血糖素的不当分泌也有助于糖尿病的高血糖。阻塞胰高血糖素作用降低了血糖，但也导致α细胞增殖和增生。我们证明，这是由于受损受损的高血液水平的氨基酸肝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循环，肝脏-ISLETα细胞轴。作为我们K01资助的调查的一部分，我们发现高水平精氨酸是高氨基酸水平对α细胞增殖和功能的影响所必需的。我们确定了 SLC7A2（CAT2）是胰岛胰岛细胞中主要的精氨酸转运蛋白。使用全球CAT2淘汰小鼠，我们发现CAT2的损失会导致α细胞增生和胰高血糖素的完全损失分泌即使是为了应对强大的分发药剂。这表明CAT2起着重要的作用在α细胞中，除了先前提出的作为一种机制，在影响膜极化之外的α细胞中精氨酸刺激的分泌。我们目前的目标是定义精氨酸刺激的α细胞的机制扩散和分泌。在AIM 1中此R01的支持下，我们将表征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）丢失Cat2表达时，胰高血糖素分泌，Ca2+动力学以及基因和蛋白质表达。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AIM 2中，我们将检查一种新型推定的精氨酸细胞表面结合蛋白，称为TM4SF4，该蛋白有选择地，并且在胰腺α细胞上强烈表达。我们将完全表征TM4SF4精氨酸结合动力学，蛋白质 α细胞中的结合伴侣，对精氨酸转运的影响以及α细胞增殖和功能的调节。一个我们工作的重要特征是，我们将使用人类胰岛翻译在鼠标胰岛中制作的发现。这些研究将为正常α细胞功能以及如何将α细胞靶向修复提供新的见解。糖尿病中的胶水分泌失调。