Neuromodulation-based treatment of diabetes: identifying anatomical and physiological pancreatic innervation targets

基于神经调节的糖尿病治疗：确定解剖学和生理学胰腺神经支配目标

• 批准号: 9752693
• 负责人: MARTHA CAMPBELL-THOMPSON
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-28 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752693
• 关键词: Adolescent; Adult; Affect; American; Anatomy; Animal Model; Antiinflammatory Effect; Autoantibodies; Autonomic nervous system; Beta Cell; Biological Neural Networks; Biology; Biomedical Engineering; Blindness; Blood Glucose; Blood flow; C-Peptide; Cause of Death; Cell physiology; Child; Clinical Endocrinology; Data; Diabetes Mellitus; Diagnosis; Disease; Endocrine; First Degree Relative; Functional disorder; Glucagon; Glucose; Health; Heart Diseases; Hormone secretion; Hormones; Human; Implant; Individual; Inflammation; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Kidney Failure; Knowledge; Maps; Methodology; Microscopy; Modeling; Nerve; Neuroanatomy; Neurobiology; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Optics; Organ; Organ Donor; Outcome; Outcome Study; Pancreas; Patients; Pattern; Peripheral; Physiological; Play; Prediabetes syndrome; Quality of life; Rattus; Regulation; Residual state; Resolution; Role; Sampling; Sensory; Serum; Specimen; Stroke; Structure of beta Cell of islet; Technology; Testing; Therapeutic; Time; United States; Work; autonomic nerve; base; comparative; cytokine; design; disease diagnosis; genetic risk factor; glucose metabolism; glucose monitor; high risk; improved; in vivo; innovation; insulin secretion; islet; nerve supply; neural circuit; neural correlate; neural stimulation; neurophysiology; neuroprosthesis; neuroregulation; neurovascular; next generation; novel; polypeptide C; programs; relating to nervous system; two-photon

Project Abstract Understanding the influence of the neural efferent and afferent regulation of β-cell health and function would be an important advancement. Although it is known that neural input plays a critical role in the health of the pancreas, details of the neuroanatomy and neurobiology of the human pancreas remains largely unexplored. It may be that T1D patients, wherein residual β-cells continue to secrete C-peptide, could benefit from neuromodulation therapies that stimulate neurovascular regrowth and result in anti-inflammatory effects in the pancreas. Furthermore, neuromodulation therapies may help to improve insulin secretion in patients with T2D or perhaps delay onset of disease for those at high risk for T1D (e.g. first-degree relative with T1D, multiple islet autoantibodies, genetic risk factors). Both knowledge of the functional neuroanatomy and enabling technologies to test this hypothesis do not currently exist. This project brings together a potent combination of experts in islet biology, neurophysiology, bioengineering, and clinical endocrinology with an innovative approach to define the comparative neuroanatomy of the human and rat pancreatic neural network. Our hypothesis is that pancreatic β-cells, functioning like peripheral neurons, maintain blood glucose levels, in part, due to the neural regulation of islet blood flow. This novel hypothesis will be tested by one specific aim: 1) To determine pancreatic neuroanatomy. These studies will enable understanding and mapping of the autonomic and sensory efferent and afferent networks in normal human and rat pancreas. Importantly, our studies will map the human pancreatic neural networks utilizing specimens already collected from human organ donors without diabetes and those with T1D or T2D using optical clearing methodologies and high resolution 3D microscopy. The outcomes of these studies will provide critical design data for logical application of next-generation neuromodulation technologies to improve islet health. This proposed work is directly in-line with the SPARC program to understand comparative neuroanatomy of the endocrine pancreas to enable neuromodulation strategies for amelioration of end organ diseases.

项目摘要 了解β细胞健康和功能的神经传出和传入调节的影响将是一个重要的进步。虽然已知神经输入在胰腺的健康中起着关键作用，但人类胰腺的神经解剖学和神经生物学的细节在很大程度上仍未被探索。可能的是，T1D患者（其中残留的β细胞继续分泌C肽）可以受益于刺激神经血管再生并在胰腺中产生抗炎作用的神经调节疗法。此外，神经调节疗法可能有助于改善T2D患者的胰岛素分泌，或者可能延迟T1D高风险患者的疾病发作（例如T1D的一级亲属、多种胰岛自身抗体、遗传风险因素）。功能神经解剖学的知识和使技术来测试这一假设目前还不存在。该项目汇集了胰岛生物学，神经生理学，生物工程和临床内分泌学专家的有效组合，采用创新方法定义人类和大鼠胰腺神经网络的比较神经解剖学。我们的假设是，胰腺β细胞，功能类似于外周神经元，维持血糖水平，部分原因是胰岛血流的神经调节。这一新的假设将通过一个特定的目的进行检验：1）确定胰腺神经解剖学。这些研究将使理解和映射的自主神经和感觉传出和传入网络在正常的人类和大鼠胰腺。重要的是，我们的研究将使用光学透明方法和高分辨率3D显微镜，利用已经从没有糖尿病的人类器官供体和T1D或T2D患者中收集的标本绘制人类胰腺神经网络。这些研究的结果将为下一代神经调节技术的逻辑应用提供关键的设计数据，以改善胰岛健康。这项拟议的工作是直接在线与ESTA计划，以了解内分泌胰腺的比较神经解剖学，使神经调节策略，改善终末器官疾病。