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

项目摘要 本研究的目的是检验Y2和Y 5受体，两种IDG合格受体， 蛋白质在决定肾上腺对低血糖的反应中起关键作用。其意义 建议是，在I型糖尿病中，低血糖发作是常见的和致残的。在糖尿病状态下， 胰岛素的释放严重减少，肾上腺素成为主要的激素， 恢复正常（“反调节反应”）。然而，在反复发作的低血 葡萄糖，肾上腺素的释放也变得大大减少。这种现象甚至发生在 非糖尿病个体，但肾上腺素释放中断的原因尚不清楚。在本提案中，我们将 测试神经肽Y的假设，它是肾上腺中肾上腺素的共同递质， 介导调节肾上腺素释放的正（Y 5）和负（Y2）反馈回路。增加 正反馈回路（依赖于Y 5）或破坏负反馈回路（依赖于Y2）可能是一种新的方法， 以防止或逆转反复低血糖的后果。 为了验证Y2和Y 5受体在该途径中的作用，我们有两个具体的目标。首先利用 BAC转基因报告小鼠和钙成像，我们将确定哪些肾上腺细胞表达Y2， Y 5受体。肾上腺髓质含有多种细胞类型。我们将调查该网站是否 受体表达涉及非神经元细胞，特别是涉及 肾上腺功能的控制 其次，我们将检验肾上腺Y2和Y 5受体是两个细胞的核心成分的假设。 在低血糖期间调节血糖水平的相互作用的反馈回路。我们将确定 嗜铬细胞释放的NPY是否导致节前神经元的快速Y 5依赖性增加→ 嗜铬细胞突触强度和肾上腺NPY合成的延迟Y2依赖性抑制。 最后，我们将测试体内选择性阻断Y2-和Y 5 R是否能暂时分开这些受体。 反馈回路外周血Y_2和Y_5R参与血糖的稳态控制 水平代表了这些蛋白质的新作用，确认它们的参与将加强 为将来研究调节该信号通路的临床效用的工作提供了理论基础。

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.