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：
8890854
负责人：
Rejji Kuruvilla
金额：
$ 19.74万
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/8890854
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 rapid growth relating to nervous system trafficking

项目摘要

DESCRIPTION (provided by applicant): 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 i 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.

描述（由申请人提供）：已知自主神经系统通过调节成人胰腺中的激素释放来调节葡萄糖稳态。朗格汉斯胰岛受到自主神经系统交感神经的丰富神经支配，并且神经支配的开始与阶段一致。然而，迄今为止，我们尚未确定交感神经支配是否有助于胰腺器官发生。交感神经的消融会导致小鼠发育过程中胰岛的形状和细胞结构出现严重缺陷（Borden 等人，2013）。交感神经切除的小鼠在生命后期表现出胰岛素分泌减少和葡萄糖不耐受。提议旨在阐明交感神经元促进胰岛形成和功能成熟获得的分子机制。根据初步发现，我们认为神经源信号是神经递质，去甲肾上腺素，通过胰腺β-肾上腺素能受体发挥作用，促进β-细胞迁移和胰岛组织。因此，我们将通过评估缺乏去甲肾上腺素能神经传递的突变小鼠体内的胰岛形成来确定去甲肾上腺素对于胰岛结构是否是必要和充分的。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），我们将确定其分子机制。通过对交感神经切除的胰岛进行基于深度测序的分析，我们观察到 PTTG1（垂体肿瘤转化基因 1）的显着下调，该基因编码据报道具有细胞骨架调节功能的蛋白质。，我们将确定 PTTG1 是否是去甲肾上腺素信号传导的转录靶标。此外，我们将评估 PTTG1 是否是 β 细胞迁移的重要调节因子。最后，我们将通过检查去甲肾上腺素对β细胞中葡萄糖传感机制和胰岛素颗粒运输的影响来阐明神经源性信号传导影响胰岛成熟的机制（目标3）。我们的研究是，它是第一个解决神经系统如何控制胰岛发育的问题，并且还将在当前治疗胰腺功能障碍的转化努力中启动新的研究方向。