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Alpha7 Nicotinic Acetylcholine Receptor Regulation of Glucagon-Like Peptide-1 Incretin Hormone Action.

Alpha7 烟碱乙酰胆碱受体对胰高血糖素样肽-1 肠促胰岛素激素作用的调节。

基本信息

批准号：
10570210
负责人：
GEORGE G HOLZ
金额：
$ 40.55万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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：
2020-04-14 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570210
关键词：
Alpha Cell Alzheimer&apos s Disease Amides Anabolism Attention Autonomic nervous system Beta Cell Blood Blood Glucose Cell Nucleus Central Nervous System Circulation Communication Deterioration Diabetic mouse Diagnosis Eating Endocrine system Enteroendocrine Cell Epidemic Etiology Fatty Acids G-Protein-Coupled Receptors GLP-I receptor GPR119 receptor GTS-21 Genetic Transcription Glucagon Goals Health Homeostasis Hormones Human In Vitro Intestinal Absorption Intestines Investigation Islets of Langerhans Killer Cells Knock-in Knockout Mice L Cells Mediating Metabolic Metabolic Diseases Modeling Molecular Mus Nervous System Neurons Nicotinic Receptors Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oral Organ Pancreas Peptide YY Phase II Clinical Trials Phenotype Physiology Process Prohormone Convertase Proprotein Convertase 1 Reflex action Regulation Role Structure of alpha Cell of islet Structure of beta Cell of islet System Technology Testing Tissues Validation acetylcholine receptor agonist afferent nerve age group alpha-bungarotoxin receptor blood glucose regulation cell type gastric inhibitory polypeptide receptor glucagon-like peptide 1 glucose tolerance hindbrain hormonal signals improved in vivo incretin hormone inhibitor insight insulin secretion islet knockout gene mortality neural initiation novel paracrine proglucagon response

项目摘要

The overall goal of this project is to establish the systems physiology of glucoregulation in which alpha 7 nicotinic acetylcholine receptors (α7nAChR) regulate the incretin hormone action of Glucagon-Like Peptide-1 (GLP-1). This project may reveal novel features of glucoregulation that are of relevance to our understanding of type 2 diabetes mellitus (T2DM) since we find that the α7nAChR agonist GTS-21 stimulates intestinal GLP-1 secretion, raises circulating levels of GLP-1, and improves glucose tolerance in mice. Thus, we propose a novel and important role for the α7nAChR in the control of glucose homeostasis by virtue of its ability to exert inter-organ control over GLP-1 secretion and GLP-1 action. To test this Hypothesis, our aims are as follows: Aim 1: We will use Cre/lox technology in combination with gene knockout or knock-in technology to determine how α7nAChR agonists lower levels of blood glucose in healthy mice or db/db and ob/ob mouse models of diabetes. A first goal is to evaluate baseline alterations of glucoregulation in tissue-specific α7nAChR knockout mice, while also assessing how α7nAChR agonist action is modified. A second goal is to identify which cell types express the GLP-1 receptor (GLP-1R) that mediates glucoregulatory actions of α7nAChR agonists. Four possibilities exist: 1) when mice are administered GTS-21 in combination with a DPP-4 inhibitor, the concentration of GLP-1 in the blood will reach high levels so that GLP-1 will act at the pancreatic β-cell GLP-1R to enhance insulin secretion, or 2) GLP-1 released from L-cells in response to GTS-21 might exert a local effect in the intestinal wall to initiate neural reflexes that stimulate insulin secretion, or 3) GTS-21 might act in the hindbrain nucleus tractus solitarius to stimulate GLP-1 release so that glucose homeostasis is improved, or 4) GTS-21 might stimulate GLP-1 release from pancreatic α-cells so that intra-islet GLP-1 will exert a paracrine hormone action at the β-cell GLP-1R. Aim 2: We will perform in vitro studies to test if GTS-21 acts exclusively at L-cells, or if it also acts at other types of enteroendocrine cells that may express the α7nAChR. For example, GTS-21 might lower levels of blood glucose by stimulating the release of GIP from K-cells so that GIP will then act at the β-cell GIP receptor to stimulate insulin secretion. Potentially, this action of GIP will be enhanced by a DPP-4 inhibitor. Since Peptide YY (PYY) is co-secreted with GLP-1 from L-cells, we may find that its release is also stimulated by GTS-21. This would be significant because PYY is important to the suppression of food intake in obesity-related T2DM. Finally, we will test for actions of GTS-21 to stimulate GLP-1 biosynthesis in L-cells and pancreatic α-cells. This possibility exists because we find that GTS-21 upregulates expression of a prohormone convertase (PC1/3) that liberates GLP-1 from proglucagon, while also upregulating expression of GPR119, a GPCR that stimulates glucagon gene transcription. It will be especially interesting to determine if the α7nAChR in pancreatic islets regulates coordinate expression of PC1/3 and GPR119 so that α-cells acquire the ability to secret GLP-1 under conditions of T2DM. Summary: Our long-term goal is to establish the systems physiology of glucoregulation under α7nAChR control.

该项目的总体目标是建立葡萄糖调节的系统生理学，其中 α7 烟碱乙酰胆碱受体 (α7nAChR) 调节胰高血糖素样肽-1 (GLP-1) 的肠促胰岛素激素作用。该项目可能揭示葡萄糖调节的新特征，这与我们对 2 型糖尿病 (T2DM) 的理解相关，因为我们发现 α7nAChR 激动剂 GTS-21 刺激肠道 GLP-1 分泌，提高 GLP-1 循环水平，并改善小鼠的葡萄糖耐量。因此，我们提出α7nAChR凭借其对GLP-1分泌和GLP-1作用发挥器官间控制的能力，在控制葡萄糖稳态中发挥新的重要作用。为了检验这一假设，我们的目标如下：目标 1：我们将使用 Cre/lox 技术结合基因敲除或敲入技术来确定 α7nAChR 激动剂如何降低健康小鼠或糖尿病 db/db 和 ob/ob 小鼠模型的血糖水平。第一个目标是评估组织特异性 α7nAChR 敲除小鼠中葡萄糖调节的基线变化，同时还评估 α7nAChR 激动剂作用是如何改变的。第二个目标是确定哪些细胞类型表达 GLP-1 受体 (GLP-1R)，介导 α7nAChR 激动剂的葡萄糖调节作用。存在四种可能性：1) 当小鼠同时服用 GTS-21 和 DPP-4 抑制剂时，血液中 GLP-1 的浓度将达到高水平，从而 GLP-1 作用于胰腺 β 细胞 GLP-1R 以增强胰岛素分泌，或 2) L 细胞响应 GTS-21 释放的 GLP-1 可能在肠壁中产生局部作用，从而启动神经反射刺激胰岛素分泌，或 3) GTS-21 可能在后脑孤束核中作用，刺激 GLP-1 释放，从而改善葡萄糖稳态，或 4) GTS-21 可能刺激胰腺 α 细胞释放 GLP-1，从而使胰岛内 GLP-1 对 β 细胞 GLP-1R 发挥旁分泌激素作用。目标 2：我们将进行体外研究，以测试 GTS-21 是否仅作用于 L 细胞，或者是否也作用于可能表达 α7nAChR 的其他类型的肠内分泌细胞。例如，GTS-21 可能通过刺激 K 细胞释放 GIP 来降低血糖水平，从而使 GIP 作用于 β 细胞 GIP 受体，刺激胰岛素分泌。 DPP-4 抑制剂可能会增强 GIP 的这种作用。由于肽 YY (PYY) 与 L 细胞的 GLP-1 共同分泌，我们可能会发现它的释放也受到 GTS-21 的刺激。这很重要，因为 PYY 对于抑制肥胖相关 T2DM 的食物摄入很重要。最后，我们将测试 GTS-21 刺激 L 细胞和胰腺 α 细胞中 GLP-1 生物合成的作用。这种可能性的存在是因为我们发现 GTS-21 上调激素原转化酶 (PC1/3) 的表达，从而从胰高血糖素原中释放 GLP-1，同时还上调 GPR119（一种刺激胰高血糖素基因转录的 GPCR）的表达。特别有趣的是确定胰岛中的 α7nAChR 是否调节 PC1/3 和 GPR119 的协调表达，从而使 α 细胞在 T2DM 条件下获得分泌 GLP-1 的能力。摘要：我们的长期目标是建立 α7nAChR 控制下的葡萄糖调节系统生理学。