Sensory Neuromodulation of Pancreatic Beta Cells

糖尿病患者胰岛分泌胰岛素的β细胞的死亡与神经元有关。因此，了解胰岛β细胞神经控制的生物学基础将揭示信息，这些信息可用于开发基于神经调节的方法来增强糖尿病患者的功能性β细胞质量。胰腺接受大量的传出副交感和交感神经元以及传入感觉神经元。虽然传出神经元在胰岛β细胞中的作用已有很好的文献记载，但感觉神经元的作用在很大程度上是未知的。胰腺感觉神经元来自迷走神经和胸脊神经，胞体分别位于结状神经节(NG)和背根神经节(DRG)。使用化学和外科手术去神经模型，我们证明了消融一部分DRG胰腺投射感觉神经元以性别依赖的方式增加了葡萄糖刺激的胰岛素分泌和葡萄糖漂移，而不改变胰岛素敏感性、身体成分和能量消耗。这些数据促使我们确定了在正常和代谢挑战条件下感觉神经元和胰腺β细胞之间串扰的分子基础。首先，我们将使用细胞内钙内流的活细胞成像、蛋白质组学和体外共培养系统来描绘感觉神经元-胰岛串扰的细胞和分子机制。我们将使用体外和体内模型来询问神经-胰岛相互联系在众所周知的血糖稳态性别差异中的意义。其次，我们将使用高通量核糖核酸深度测序的方法来识别迷走神经和脊髓感觉神经来源的神经肽和生长因子，这些神经肽和生长因子调节胰岛素抵抗状态下适应性β细胞的扩张和活性。高分辨率成像设备(PanCLARITY)将被用来准确地定位胰腺β细胞和新发现的感觉神经元标记之间的相互作用。最后，我们将使用体外和体内模型来确定新的感觉来源的信号分子在小鼠和人类β细胞的增殖和功能中的作用和作用机制。总之，这些研究将揭开传入神经元和胰岛β细胞之间独特相互作用的分子基础，并将为设计基于神经药理学和神经调节的策略以提高糖尿病患者的功能性β细胞质量提供高价值的生物学数据。

The demise of pancreatic islet insulin-secreting β cells in diabetes has a neuronal component. Therefore, understanding the biology underlying the neuronal control of islet β cells will unravel information that can be leveraged to develop neuromodulation-based methods to enhance functional β-cell mass in individuals with diabetes. The pancreas receives a generous supply of efferent parasympathetic and sympathetic neurons and afferent sensory neurons. While the effect of efferent neurons in islet β cells is well documented, the role of sensory neurons is largely unknown. The pancreatic sensory neurons emanate from the vagal and thoracic spinal nerves with cell bodies lying in the nodose ganglia (NG) and dorsal root ganglia (DRG), respectively. Using chemical and surgical denervation models, we demonstrated that ablation of a subset of DRG pancreas-projecting sensory neurons enhanced glucose-stimulated insulin secretion and glucose excursion – in a sex-dependent manner – without alterations in insulin sensitivity, body composition and energy expenditure. These data prompted us to determine the molecular foundation of the crosstalk between sensory neurons and pancreatic β cells under normal and metabolically challenged conditions. First, we will use live-cell imaging of intracellular calcium influx, proteomics and in vitro co-culture systems to delineate the cellular and molecular mechanisms of the sensory neuron-islet crosstalk. We will use in vitro and in vivo models to interrogate the significance of the neuro-islet intercommunication in the well-known sex difference in glucose homeostasis. Second, we will use high-throughput RNA deep sequencing approach to identify vagal and spinal sensory-derived neuropeptides and growth factors modulating adaptive β-cell expansion and activity in insulin-resistant states. High-resolution imaging modality (PanCLARITY) will be used to map with accuracy the interactions between pancreatic β cells and the newly identified sensory neuronal markers. Finally, we will use in vitro and in vivo models to define the role and mechanism of action of novel sensory-derived signaling molecules in proliferation and function of mouse and human β cells. Together, these studies will unravel the molecular foundation of the unique interactions between afferent neurons and islet β cells and will provide high-value biological data to design neuropharmacology- and neuromodulation-based strategies to enhance functional β-cell mass in patients with diabetes.