Mapping Stomach Autonomic Circuitry and Function for Neuromodulation of Gastric Disorders

绘制胃自主神经回路和功能以调节胃部疾病的神经调节

• 批准号: 9286967
• 负责人: TERRY L. POWLEY
• 金额: $ 200.44万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-24 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286967
• 关键词: Action Potentials; Acute; Address; Adverse effects; Algorithms; Animal Model; Animals; Architecture; Axon; Biological Assay; Biological Neural Networks; Brain Stem; Chemicals; Chronic; Clinic; Clinical; Communities; Complex; Devices; Digestion; Disease; Eating; Eating Disorders; Educational workshop; Electrodes; Electrolytes; Elements; Epidemic; Equipment and supply inventories; Family suidae; Feedback; Fiber; Foundations; Functional Magnetic Resonance Imaging; Future; Gastric Emptying; Gastroesophageal reflux disease; Gastroparesis; Generations; Growth; Hormones; Human; Image; Indium; Ingestion; Institution; Investigation; Knowledge; Label; Laboratories; Lead; Learning; Liquid substance; Location; Magnetic Resonance Imaging; Maps; Measures; Medical Research; Medicine; Modeling; Molecular; Monitor; Nausea and Vomiting; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Organ; Outcome; Patients; Pattern; Peripheral Nerves; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phenotype; Physiological; Physiology; Protocols documentation; Qualifying; Rattus; Reflex action; Reflux; Refractory; Regulation; Reporting; Research; Research Personnel; Resolution; Resource Sharing; Response to stimulus physiology; Role; Secondary to; Series; Signal Transduction; Site; Smooth Muscle; Specimen; Stimulus; Stomach; Stomach Diseases; Taxonomy; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Translations; United States National Institutes of Health; Validity and Reliability; Wireless Technology; clinical application; combat; connectome; data archive; design; diabetic gastroparesis; disorder control; feeding; implantable device; innovation; nerve supply; neural circuit; neuroregulation; next generation; pre-clinical; relating to nervous system; research study; response; sound; standard measure

Project Summary Two series of complementary experiments, conducted by our exceptionally qualified team of 11 investigators from eight state-of-the-art laboratories at four institutions, will close critical gaps in the current characterization of the autonomic connectome controlling stomach function. These proposed synergistic anatomical and functional investigations will form the needed foundation for neuromodulation protocols that can correct shortcomings in past, first-generation bioelectronic attempts to ameliorate and monitor gastric disorders. Building on recent advances in mapping of vagal circuits, many reported by our research team, SA 1 will finish inventories of the efferent and afferent terminal phenotypes, analyze their collateral specializations, establish their regional distributions, and identify chemical taxonomies of their target tissues. We will also compare the neural circuitry of the human (and pig, an ideal large animal preclinical proof-of-principle model) stomach with that of the rat model to facilitate future translational extrapolations. The analyses of SA 1 will use a suite of high-definition neural tracing, immunohistochemical and molecular protocols, along with advanced imaging and morphometric techniques, that our team has adapted to autonomic circuits. SA 1 will focus on those elements in gastric neural network that may be most relevant to informing SA 2 and identify additional localized sites in the stomach wall where focal stimulation will have strong therapeutic potential. In functional assessments, SA 2 will identify optimal locations for both highly selective vagal stimulation (VNS) and precise surgical placement between the exit of the vagus from the brainstem and the target sites of the axons within the stomach wall and will determine the best stimulation protocols for augmenting gastric physiology. SA 2 will use state-of-the-art closed-loop stimulator technologies, algorithms, and electrodes (previously designed and robustly proven by investigators on our research team) and assess the reliability, validity, and stability of the VNS by employing a battery (≥ 6) of acute, short-term, and long-term non-invasive endpoints. The team will use data archiving and resource sharing platforms that are universally accessible to all research and medical communities.

项目概要 由 11 名研究人员组成的优秀团队进行了两个系列的补充实验 来自四个机构的八个最先进的实验室，将弥补当前表征中的关键差距 控制胃功能的自主连接组。这些提出的协同解剖学和 功能研究将为神经调节方案奠定必要的基础，该方案可以纠正 过去第一代生物电子改善和监测胃病的尝试存在缺陷。 基于我们研究团队报告的迷走神经回路映射的最新进展，SA 1 将完成 传出和传入末端表型的清单，分析它们的附带专业化，建立 它们的区域分布，并确定其目标组织的化学分类法。我们还将比较 人类（和猪，一种理想的大型动物临床前原理验证模型）胃的神经回路 大鼠模型的模型，以促进未来的平移外推。 SA 1 的分析将使用一套 高清神经追踪、免疫组织化学和分子方案，以及先进的成像和 我们的团队已将形态测量技术应用于自主电路。 SA 1 将重点关注这些要素 在胃神经网络中，这可能与通知 SA 2 最相关并识别出其他局部位点 胃壁，局部刺激将具有强大的治疗潜力。在功能评估中，SA 2 将确定高选择性迷走神经刺激 (VNS) 和精确手术放置的最佳位置 在脑干迷走神经出口和胃壁内轴突的目标位置之间 将确定增强胃生理学的最佳刺激方案。 SA 2将使用最先进的 闭环刺激器技术、算法和电极（之前设计并经过严格验证） 我们研究团队的研究人员）并通过采用以下方法评估 VNS 的可靠性、有效性和稳定性： 急性、短期和长期非侵入性终点的电池组（≥ 6）。该团队将使用数据归档和 所有研究和医学界都可以普遍访问的资源共享平台。