Determining the role of the adrenal Y2 and Y5 receptors in the prevention of hypoglycemia

确定肾上腺 Y2 和 Y5 受体在预防低血糖中的作用

• 批准号: 9813589
• 负责人: MATTHEW WHIM
• 金额: $ 14.7万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813589
• 关键词: 3-Dimensional; Adrenal Glands; Adrenal Medulla; Anatomy; Bacterial Artificial Chromosomes; Blood Glucose; Calcium; Cells; Chromaffin Cells; Clinical; Dangerousness; Effectiveness; Epinephrine; Fasting; Feedback; Future; Genetic; Glucagon; Hormonal; Hormones; Human; Hypoglycemia; Image; Immune; Impairment; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Location; Mediating; Modeling; Mus; Neuroglia; Neurons; Neurosecretory Systems; Pathologic; Pathway interactions; Peripheral; Pharmacology; Physiological; Play; Population; Prevention; Proteins; Reflex action; Reporter; Role; Signal Pathway; Site; Synapses; Testing; Transgenic Organisms; Work; cell type; combinatorial; diabetic; euglycemia; experimental study; falls; glucose production; glycemic control; in vivo; macrophage; neuropeptide Y; neuropeptide Y5 receptor; non-diabetic; prevent; receptor; receptor expression; response; tool; transmission process; 3-Dimensional; Adrenal Glands; Adrenal Medulla; Anatomy; Bacterial Artificial Chromosomes; Blood Glucose; Calcium; Cells; Chromaffin Cells; Clinical; Dangerousness; Effectiveness; Epinephrine; Fasting; Feedback; Future; Genetic; Glucagon; Hormonal; Hormones; Human; Hypoglycemia; Image; Immune; Impairment; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Location; Mediating; Modeling; Mus; Neuroglia; Neurons; Neurosecretory Systems; Pathologic; Pathway interactions; Peripheral; Pharmacology; Physiological; Play; Population; Prevention; Proteins; Reflex action; Reporter; Role; Signal Pathway; Site; Synapses; Testing; Transgenic Organisms; Work; cell type; combinatorial; diabetic; euglycemia; experimental study; falls; glucose production; glycemic control; in vivo; macrophage; neuropeptide Y; neuropeptide Y5 receptor; non-diabetic; prevent; receptor; receptor expression; response; tool; transmission process

PROJECT SUMMARY The objective of the proposed study is to test the hypothesis that Y2 and Y5 receptors, two IDG-eligible proteins play a critical role in determining the adrenal response to hypoglycemia. The significance of this proposal is that in type I diabetes, hypoglycemic episodes are common and disabling. In the diabetic state, the release of insulin is severely reduced and epinephrine becomes the main hormone responsible for restoring euglycemia (the “counter-regulatory response”). However after repeated episodes of low blood glucose, the release of epinephrine also becomes substantially reduced. This phenomenon occurs even in non-diabetic individuals, but why epinephrine release is disrupted is not known. In this proposal we will test the hypothesis that neuropeptide Y, which is a co-transmitter with epinephrine in the adrenal gland, mediates positive (Y5) and negative (Y2) feedback loops that modulate epinephrine release. Increasing the positive (Y5-dependent) or disrupting the negative (Y2-dependent) feedback loops may be a new way to prevent or reverse the consequences of repetitive hypoglycemia. To validate the role of the Y2 and Y5 receptors in this pathway we have two specific aims. First, using BAC transgenic reporter mice and calcium imaging we will determine which adrenal cells express Y2 and Y5 receptors. The adrenal medulla contains a variety of cell types. We will investigate whether the site of receptor expression involves non-neuronal cells, in particular a population of macrophages implicated in the control of adrenal function. Second, we will test the hypothesis that the adrenal Y2 and Y5 receptors are core components of two interacting feedback loops that modulate blood glucose levels during hypoglycemia. We will determine whether NPY release from chromaffin cells leads to a rapid Y5-dependent increase in preganglionic → chromaffin cell synaptic strength and a delayed Y2-dependent suppression of adrenal NPY synthesis. Finally, we will test whether selective blockade of Y2- and Y5R’s in vivo can temporally separate these feedback loops. The involvement of peripheral Y2 and Y5R’s in the homeostatic control of blood glucose levels represents a new role for these proteins and confirming their involvement would strengthen the rationale for future work investigating the clinical utility of modulating this signaling pathway.

项目摘要 拟议的研究的目的是检验Y2和Y5受体，两个IDG资格的假设 蛋白质在确定对低血糖的肾上腺反应中起关键作用。这一点的意义 建议是在I型糖尿病中，降血糖发作是常见且残疾的。在糖尿病状态下， 胰岛素的释放严重降低，肾上腺素成为负责 恢复尤利西亚（“反调节反应”）。但是，在重复的低血分发作之后 葡萄糖，肾上腺素的释放也大大降低。这种现象甚至在 非糖尿病的个体，但为什么尚不清楚肾上腺素释放的原因。在这个建议中，我们将 检验以下假设：神经肽Y是与肾上腺中肾上腺素的co肽Y 介导调节肾上腺素释放的阳性（Y5）和负（Y2）反馈回路。增加 正（依赖于Y5）或破坏负面（依赖Y2）的反馈回路可能是一种新方法 预防或扭转重复性低血糖的后果。 为了验证Y2和Y5受体在该途径中的作用，我们有两个具体的目标。首先，使用 BAC转基因报告基因小鼠和钙成像，我们将确定哪些肾上腺细胞表达Y2和 Y5受体。肾上腺髓质包含多种细胞类型。我们将调查是否 受体表达涉及非神经元细胞，特别是在 肾上腺功能的控制。 其次，我们将检验以下假设：肾上腺Y2和Y5受体是两个的核心成分 相互作用的反馈回路可在低血糖期间调节血糖水平。我们将确定 NPY从铬蛋白细胞中释放是否导致孕妇的Y5依赖性迅速依赖→ 铬蛋白细胞突触强度和延迟Y2依赖性抑制肾上腺NPY合成。 最后，我们将测试Y2-和Y5R的体内的选择性封锁是否可以暂时分开 反馈循环。外围Y2和Y5R参与血糖的稳态控制 水平代表了这些蛋白质的新作用，并确认其参与将加强 未来工作的基本原理调查调节该信号通路的临床实用性。