Sympathetic innervation in pancreatic development and function

已知自主神经系统通过以下方式调节葡萄糖稳态： 调节成年胰腺的激素释放。胰岛是 由自主神经系统的交感神经丰富支配， 神经支配的发生与胰岛的生长和成熟阶段相一致 胰腺然而，交感神经支配是否有助于胰腺器官发生 到目前为止还没有定义。我们最近报道了切除交感神经 导致胰岛的形状和细胞结构的严重缺陷， 在小鼠中的发育（Borden et.等人，2013）。交感神经切除的小鼠表现出降低的 胰岛素分泌和葡萄糖耐受不良。因此，这一总体目标 一项旨在阐明交感神经元 促进胰岛形成和功能成熟的获得。 基于初步发现，我们假设神经源性信号是 神经递质，去甲肾上腺素，通过胰腺肾上腺素能受体作用， 促进胰岛细胞迁移和胰岛组织化。因此，我们将确定， 去甲肾上腺素是必要的和足够的胰岛结构，通过评估胰岛 在缺乏去甲肾上腺素能神经传递的突变小鼠体内形成，以及 通过检测去甲肾上腺素对体外细胞迁移和聚集的影响， (Aim 1）。在目标2中，我们将确定去甲肾上腺素 信号传导影响胰岛结构。通过基于深度测序的 在交感神经切除的胰岛中，我们观察到PTTG 1（垂体 肿瘤转化基因1），其编码据报道具有细胞骨架的蛋白质- 监管职能。因此，我们将确定PTTG 1是否是一个转录靶点， 去甲肾上腺素信号此外，我们将评估PTTG 1是否是一个重要的 细胞迁移的调节因子，采用可用的PTTG 1敲除小鼠。最后我们 将阐明神经源性信号影响胰岛的机制， 通过检查去甲肾上腺素对葡萄糖敏感的影响， 机械和胰岛素颗粒运输在？-细胞（目的3）。我们的重要性 这项研究的一个重要意义是，它是第一个解决神经系统如何控制胰岛的研究。 发展，也将启动一个新的研究路线，在目前的翻译工作 来治疗胰腺功能障碍

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.