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.

众所周知，自主神经系统通过以下方式调节葡萄糖稳态：调节成人胰腺中的胰岛激素释放。受自主神经系统交感神经的丰富支配和发作神经支配的过程与发育中的胰岛生长和成熟阶段一致然而，交感神经支配是否有助于胰腺器官发生。到目前为止，我们还没有定义交感神经的消融。导致胰岛形状和细胞结构的严重缺陷小鼠的发育（Borden et. al, 2013）。生命后期的胰岛素分泌和葡萄糖不耐症因此是该项目的总体目标。提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的获得。根据初步发现，我们发现神经源信号是神经递质，去甲肾上腺素，通过胰腺发挥作用 ¿ - 肾上腺素能受体推动 -细胞迁移和胰岛组织因此，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要且充分的缺乏去甲肾上腺素能神经传递的突变小鼠体内的形成，以及通过检查去甲肾上腺素对 ¿ 的影响- 细胞体外迁移和聚集（目标 1）在目标 2 中，我们将确定去甲肾上腺素的分子机制。通过基于深度测序的分析来影响胰岛结构。在交感神经切除的胰岛中，我们观察到 PTTG1（垂体肿瘤转化基因 1)，编码据报道具有细胞骨架的蛋白质因此，我们将确定 PTTG1 是否是 PTTG1 的转录靶标。此外，我们将评估 PTTG1 是否是必需的。的调节器 ¿ -细胞迁移，采用可用的 PTTG1 敲除小鼠。将阐明神经源性信号传导影响胰岛的机制通过检查去甲肾上腺素对葡萄糖感应的影响来成熟机械和胰岛素颗粒贩运 ¿ -细胞（目标 3）。研究表明，它是第一个解决神经系统如何控制胰岛的问题发展，并将在当前的转化工作中启动新的研究领域治疗胰腺功能障碍。