Sensory Neuromodulation of Pancreatic Beta Cells

胰腺β细胞的感觉神经调节

基本信息

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
项目类别：
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

项目摘要

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 细胞神经元控制的生物学原理将揭示可用于开发基于神经调节的方法来增强功能性 β 细胞量的信息。在糖尿病患者中，胰腺接收大量的传出副交感神经元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 细胞中的作用已得到充分证明，但感觉神经元的作用却很丰富。胰腺感觉神经元起源于迷走神经和胸脊神经，细胞体分别位于结状神经节（NG）和背根神经节（DRG），我们使用化学和手术去神经模型证明了子集的消融。 DRG 胰腺投射感觉神经元以性别依赖性方式增强葡萄糖刺激的胰岛素分泌和葡萄糖偏移，而不会改变胰岛素敏感性、身体成分和能量消耗。促使我们确定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流入的活细胞成像、蛋白质组学和体外共培养系统来描绘细胞。我们将使用体外和体内模型来探讨神经岛相互通讯在众所周知的葡萄糖稳态性别差异中的重要性。高通量 RNA 深度测序方法可识别迷走神经和脊髓感觉源性神经肽和生长因子，在胰岛素抵抗状态下调节适应性 β 细胞扩张和活性，高分辨率成像模式 (PanCLARITY) 将用于准确绘制相互作用图。最后，我们将使用体外和体内模型来确定新型感觉衍生信号分子在小鼠和人类 β 细胞增殖和功能中的作用和作用机制。，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来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细胞量。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis.

GLP-1 的状态依赖性中枢突触调节对于能量稳态至关重要。

DOI：
10.21203/rs.3.rs-3929981/v1
发表时间：
2024
期刊：
Research square
影响因子：
0
作者：
Wang,Le;Savani,Rohan;Bernabucci,Matteo;Lu,Yi;Singh,Ishnoor;Xu,Wei;ElOuaamari,Abdelfattah;Wheeler,MichaelB;Grill,HarveyJ;Rossi,MarkA;Pang,ZhipingP
通讯作者：
Pang,ZhipingP