Mapping Stomach Autonomic Circuitry and Function for Neuromodulation of Gastric Disorders

项目摘要 两系列互补实验，由我们非常合格的11名调查人员组成的团队进行 来自四个机构的八个最先进的实验室，将填补目前表征方面的关键差距 控制胃功能的自主神经连接体。这些建议的协同解剖和 功能研究将为神经调节方案奠定必要的基础，使其能够 过去，第一代生物电子尝试改善和监测胃病的缺点。 基于迷走神经环路图谱的最新进展，我们的研究团队报道了许多，SA 1将完成 清点传出和传出终端表型，分析它们的侧枝专门化，建立 它们的区域分布，并确定其目标组织的化学分类。我们还将比较 人(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 以便于将来的平移外推。SA 1的分析将使用一套 高清晰度神经追踪、免疫组织化学和分子协议，以及先进的成像和 形态测量技术，我们的团队已经适应了自主神经回路。SA 1将专注于这些元素 在胃神经网络中，可能与通知SA-2和识别更多定位部位最相关 胃壁的局部刺激将具有很强的治疗潜力。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 迷走神经从脑干出口与胃壁内轴突的靶部位之间 将确定增强胃生理功能的最佳刺激方案。SA 2将使用最先进的 闭环刺激器技术、算法和电极(以前设计并由 我们研究团队中的研究人员)，并通过采用 急性、短期和长期非侵入性终端的电池(≥6)。该团队将使用数据归档和 所有研究和医学界普遍可访问的资源共享平台。

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.