Sympathetic innervation in pancreatic development and function

胰腺发育和功能中的交感神经支配

基本信息

批准号：
8751267
负责人：
Rejji Kuruvilla
金额：
$ 20.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-11 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751267
关键词：
Ablation Address Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Adult Architecture Area Attenuated Autoimmune Process Autonomic nervous system Behavior Behavior monitoring Blood Glucose Cell Aggregation Cell Culture Techniques Cell membrane Cell physiology Cells Coculture Techniques Complement Cytoskeleton Defect Development Diabetes Mellitus Disease Docking Down-Regulation Electrons Embryo Exhibits Failure Functional disorder Glucose Glucose Intolerance Glucose Transporter Goals Growth Health Hormones Human Image Analysis In Vitro Indium Injury Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knockout Mice Life Microscopic Molecular Mus Mutant Strains Mice Nerve Nerve Tissue Nervous system structure Neuronal Dysfunction Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Null Lymphocytes Organogenesis PTTG1 gene Pancreas Pathogenesis Pathway interactions Prevalence Propranolol Proteins Reporting Research Shapes Signal Pathway Signal Transduction Staging Sympathectomy Testing Work adrenergic base blood glucose regulation cell motility chemical genetics deep sequencing endocrine pancreas development glucose metabolism impaired glucose tolerance in vitro Assay in vivo insight insulin granule insulin secretion islet mutant nerve supply neurotransmission noradrenergic public health relevance rapid growth relating to nervous system trafficking

项目摘要

The autonomic nervous system is known to regulate glucose homeostasis by modulating hormone release in the adult pancreas. Pancreatic islets of Langerhans are richly innervated by sympathetic nerves of the autonomic nervous system and the onset of innervation is coincident with stages of islet growth and maturation in the developing pancreas. Yet, whether, sympathetic innervation contributes to pancreas organogenesis has not been defined so far. We recently reported that ablation of sympathetic nerves results in profound defects in the shape and cyto-architecture of islets during development in mice (Borden et. al, 2013). Sympathectomized mice exhibit reduced insulin secretion and glucose intolerance later in life. Thus, the overall goal of this proposal is to elucidate the molecular mechanisms by which sympathetic neurons promote islet formation and the acquisition of functional maturity. Based on preliminary findings, we hypothesize that the nerve-derived signal is the neurotransmitter, norepinephrine, that acts via pancreatic ¿-adrenergic receptors to promote ¿-cell migration and islet organization. Thus, we will determine if norepinephrine is necessary and sufficient for islet architecture by assessing islet formation in vivo in mutant mice that lack noradrenergic neurotransmission, as well as by examining the effects of norepinephrine on ¿-cell migration and aggregation in vitro (Aim 1). In Aim 2, we will identify the molecular mechanisms by which norepinephrine signaling influences islet architecture. By deep sequencing-based profiling of sympathectomized islets, we observed a dramatic down-regulation of PTTG1 (pituitary tumor-transforming gene 1), that encodes for a protein reported to have cytoskeleton- regulatory functions. Thus, we will determine if PTTG1 is a transcriptional target of norepinephrine signaling. Additionally, we will assess whether PTTG1 is an essential regulator of ¿-cell migration, employing available PTTG1 knockout mice. Finally, we will elucidate the mechanisms by which nerve-derived signaling influences islet maturation by examining the effects of norepinephrine on the glucose-sensing machinery and insulin granule trafficking in ¿-cells (Aim 3). The significance of our studies is that it is the first to address how the nervous system controls islet development and will also initiate a new line of research in current translational efforts to treat pancreatic dysfunction.

已知自主神经系统通过在成年胰腺中调节马龙释放。 Langerhans的胰岛是自主神经系统和发作的交感神经系统的支配很丰富神经支配与发展中的胰岛生长和成熟阶段是一致的胰腺。然而，同情神经是否有助于胰腺器官发生到目前为止尚未定义。我们最近报道说交感神经的消融在胰岛的形状和细胞结构中产生深远的缺陷小鼠的发育（Borden等，2013）。交感的小鼠暴露了胰岛素的分泌和葡萄糖肠子以后生命。那是总体目标建议是阐明交感神经元的分子机制促进胰岛形成和功能成熟度的获取。根据初步发现，我们假设神经衍生的信号是神经递质，去甲肾上腺素，通过胰腺疫苗作用�-肾上腺素接收器促进 - 细胞迁移和胰岛组织。那我们将确定是否通过评估胰岛，去甲肾上腺素对于胰岛结构是必需的，足以满足缺乏去甲肾上腺素能神经传递的突变小鼠中的体内形成通过检查去甲肾上腺素对体外细胞迁移和聚集的影响（目标1）。在AIM 2中，我们将确定去甲肾上腺素的分子机制信号影响胰岛架构。通过基于深度测序的分析交感神经胰岛，我们观察到PTTG1的戏剧性下调（垂体肿瘤转化基因1），该基因编码据报道具有细胞骨架的蛋白质监管功能。这，我们将确定PTTG1是否是去甲肾上腺素信号传导。此外，我们将评估PTTG1是否是必不可少的 � -细胞迁移，采用可用的PTTG1基因敲除小鼠。最后，我们将阐明神经衍生信号传导胰岛的机制通过检查去甲肾上腺素对葡萄糖感应的影响成熟机械和胰岛素颗粒贩运�Cells（AIM 3）。我们的意义研究是，它是第一个解决神经系统如何控制胰岛的问题开发，还将在当前的翻译工作中启动新的研究系列治疗胰腺功能障碍。