Sensory Neuromodulation of Pancreatic Beta Cells

胰腺β细胞的感觉神经调节

• 批准号: 10886267
• 负责人: Abdelfattah El Ouaamari
• 金额: $ 41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10886267
• 关键词: Ablation; Affect; Afferent Neurons; Autoimmunity; Beta Cell; Biological; Biological Assay; Biology; Body Composition; Calcium; Cell Proliferation; Cell physiology; Cells; Cellular Stress; Central Nervous System; Chemicals; Chest; Clinical; Coculture Techniques; Data; Denervation; Detection; Development; Diabetes Mellitus; Disease; Efferent Neurons; Energy Metabolism; Etiology; Excision; Exhibits; FGF3 gene; Failure; Female; Foundations; Functional disorder; Ganglia; Gene Expression; Genetic; Glucagon; Glucose; Goals; Gonadal Steroid Hormones; Growth Factor; Harvest; Hormones; Human; Hyperplasia; Immunofluorescence Microscopy; Immunologic Deficiency Syndromes; In Vitro; Individual; Insulin; Insulin Resistance; Islets of Langerhans; Islets of Langerhans Transplantation; Link; Literature; Maps; Mediating; Metabolic; Methods; Modality; Modeling; Molecular; Mus; Neurons; Neuropeptides; Neuropharmacology; Nociceptors; Nodose Ganglion; Operative Surgical Procedures; Pain; Pain Threshold; Pancreas; Patients; Perception; Peripheral; Play; Prevalence; Progesterone; Proliferating; Proteomics; RNA; Recombinants; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Sensory Ganglia; Sex Bias; Sex Chromosomes; Sex Differences; Signal Pathway; Signaling Molecule; Specimen; Spinal; Spinal Ganglia; Spinal cord injury; Spinal nerve structure; Streptozocin; Structure of beta Cell of islet; System; Systems Biology; Techniques; Testosterone; Time; Tissues; Translational Research; Vertebral column; base; blood glucose regulation; cell regeneration; deep sequencing; design; diabetic; experimental study; functional restoration; genetic approach; glucagon-like peptide 1; high resolution imaging; imaging modality; in vivo Model; insulin secretion; insulin sensitivity; islet; live cell imaging; male; men; mouse model; nerve supply; neural; neurochemistry; neuron component; neuroregulation; neurosensory; novel; pain perception; pharmacologic; response; sensory mechanism; sensory system; sex; transcriptome sequencing; type I and type II diabetes; Ablation; Affect; Afferent Neurons; Autoimmunity; Beta Cell; Biological; Biological Assay; Biology; Body Composition; Calcium; Cell Proliferation; Cell physiology; Cells; Cellular Stress; Central Nervous System; Chemicals; Chest; Clinical; Coculture Techniques; Data; Denervation; Detection; Development; Diabetes Mellitus; Disease; Efferent Neurons; Energy Metabolism; Etiology; Excision; Exhibits; FGF3 gene; Failure; Female; Foundations; Functional disorder; Ganglia; Gene Expression; Genetic; Glucagon; Glucose; Goals; Gonadal Steroid Hormones; Growth Factor; Harvest; Hormones; Human; Hyperplasia; Immunofluorescence Microscopy; Immunologic Deficiency Syndromes; In Vitro; Individual; Insulin; Insulin Resistance; Islets of Langerhans; Islets of Langerhans Transplantation; Link; Literature; Maps; Mediating; Metabolic; Methods; Modality; Modeling; Molecular; Mus; Neurons; Neuropeptides; Neuropharmacology; Nociceptors; Nodose Ganglion; Operative Surgical Procedures; Pain; Pain Threshold; Pancreas; Patients; Perception; Peripheral; Play; Prevalence; Progesterone; Proliferating; Proteomics; RNA; Recombinants; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Sensory Ganglia; Sex Bias; Sex Chromosomes; Sex Differences; Signal Pathway; Signaling Molecule; Specimen; Spinal; Spinal Ganglia; Spinal cord injury; Spinal nerve structure; Streptozocin; Structure of beta Cell of islet; System; Systems Biology; Techniques; Testosterone; Time; Tissues; Translational Research; Vertebral column; base; blood glucose regulation; cell regeneration; deep sequencing; design; diabetic; experimental study; functional restoration; genetic approach; glucagon-like peptide 1; high resolution imaging; imaging modality; in vivo Model; insulin secretion; insulin sensitivity; islet; live cell imaging; male; men; mouse model; nerve supply; neural; neurochemistry; neuron component; neuroregulation; neurosensory; novel; pain perception; pharmacologic; response; sensory mechanism; sensory system; sex; transcriptome sequencing; type I and type II diabetes

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.

糖尿病中胰岛分泌β细胞的胰岛胰岛素的灭亡具有神经元成分。因此，了解胰岛β细胞神经元控制的生物学将揭开可以利用的信息，这些信息可以利用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。胰腺获得了有效的副交感神经和交感神经元以及传入的感觉神经元的大量供应。虽然有效神经元在胰岛细胞中的作用有充分的文献证明，但感觉神经元的作用在很大程度上尚不清楚。胰腺感觉神经元分别源自迷走神经和胸椎神经，分别位于淋巴结神经节（NG）和背根神经节（DRG）中。使用化学和外科神经神经模型，我们证明了DRG胰腺侵蚀的感觉神经元的一部分消融增强了葡萄糖刺激的胰岛素分泌和葡萄糖偏移，并以性依赖性方式 - 没有改变胰岛素敏感性，身体成分和能量支出。这些数据促使我们确定在正常和代谢挑战的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影响，蛋白质组学和体外共培养系统的活细胞成像来描述感觉神经元islet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 - 牢房间交往对葡萄糖稳态中众所周知的性别差异的重要性。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柱感觉衍生的神经肽和生长因子调节适应性β细胞扩张和抗胰岛素耐药性状态的活性。高分辨率成像方式（胰腺）将用于准确地绘制胰腺β细胞与新鉴定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定义新型感觉信号分子在小鼠和人β细胞的增殖和功能中的作用和机理。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基于神经调节的策略，以增强糖尿病患者的功能性β细胞质量。