Sympathetic innervation in pancreatic development and function

胰腺发育和功能中的交感神经支配

• 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
• 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

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的动态平衡 调节成人胰腺的激素释放。朗格汉斯的胰岛是 富于交感神经的自主神经系统及其发病 神经支配的变化与胰岛发育成熟阶段相吻合。 胰腺。然而，交感神经是否参与了胰腺器官的发生 到目前为止还没有定义。我们最近报道了交感神经的消融 导致胰岛形态和细胞结构的严重缺陷 小鼠的发育(Borden et.Al，2013)。交感神经切除的小鼠表现出减少 晚年的胰岛素分泌和葡萄糖不耐受。因此，这一计划的总体目标是 建议阐明交感神经元 促进胰岛形成和功能成熟度的获得。 根据初步发现，我们假设神经衍生信号是 神经递质，去甲肾上腺素，通过胰腺肾上腺素能受体作用于 促进细胞迁移和胰岛组织。因此，我们将确定是否 通过评估胰岛来评估去甲肾上腺素对胰岛构筑的充要条件 缺乏去甲肾上腺素能神经传递的突变小鼠体内形成 通过检测去甲肾上腺素对体外细胞迁移和聚集的影响 (目标1)。在目标2中，我们将确定去甲肾上腺素的分子机制 信号会影响小岛的架构。通过基于深度测序的分析 在切除交感神经的胰岛中，我们观察到Pttg1(垂体)的表达显著下调 肿瘤转化基因1)，编码一种蛋白质，据报道具有细胞骨架- 监管职能。因此，我们将确定Pttg1是否是 去甲肾上腺素信号。此外，我们将评估Pttg1是否是必需的 ？细胞迁移的调节器，使用可用的Pttg1基因敲除小鼠。最后，我们 将阐明神经衍生信号影响胰岛的机制 去甲肾上腺素对葡萄糖感受性的影响 机械和胰岛素颗粒在细胞内的运输(目标3)。我们的重要意义在于 研究表明，这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一条新的研究路线 治疗胰腺功能障碍。