Sensory Neuromodulation of Pancreatic Beta Cells

糖尿病中胰岛胰岛素分泌β细胞的死亡具有神经元成分。因此，了解神经元控制胰岛β细胞的生物学基础将揭示可用于开发基于神经调节的方法以增强糖尿病个体中功能性β细胞群的信息。胰腺接受大量的传出副交感神经和交感神经元以及传入感觉神经元的供应。虽然传出神经元在胰岛β细胞中的作用已得到充分证实，但感觉神经元的作用在很大程度上尚不清楚。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）。使用化学和手术去神经模型，我们证明了DRG胰腺投射感觉神经元的子集的消融增强了葡萄糖刺激的胰岛素分泌和葡萄糖波动-以性别依赖的方式-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，我们将使用活细胞成像的细胞内钙流入，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在葡萄糖稳态中众所周知的性别差异中神经-胰岛相互通信的意义。其次，我们将使用高通量RNA深度测序方法来鉴定迷走神经和脊髓感觉源性神经肽和生长因子，其调节胰岛素抵抗状态下的适应性β细胞扩增和活性。将使用高分辨率成像模式（Panamidity）准确绘制胰腺β细胞与新鉴定的感觉神经元标志物之间的相互作用。最后，我们将使用体外和体内模型来确定新型感觉源性信号分子在小鼠和人β细胞增殖和功能中的作用和作用机制。总之，这些研究将揭示传入神经元和胰岛β细胞之间独特相互作用的分子基础，并将提供高价值的生物学数据，以设计基于神经药理学和神经调节的策略，以增强糖尿病患者的功能性β细胞群。

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.