Foundational Mapping of the Neural Circuits that Control Intrinsic Lung Function

项目概要 肺是一个神经支配丰富的器官。强有力的证据，包括我们最近的发现，表明 神经元控制在肺部对环境的基本反应（包括免疫活动）中发挥着核心作用，如 以及影响气导和肺血的气道和血管平滑肌张力 压力，分别。然而，神经系统如何影响肺功能的全部范围仍然存在 目前尚不清楚，而且对支配肺部的神经元的解剖学和分子特征知之甚少。 在这里，我们建议使用尖端的基于病毒的电路追踪、单细胞转录组和单倍体 ES 细胞 - 基于基因组编辑技术：1）标记肺神经神经元； 2）确定它们的定位和 投影图案； 3）生成敲入小鼠系，为肺神经调节奠定基础 功能。在小鼠中产生的结果将在人类活检样本中进行测试，以区分保守性与保守性 物种特异性机制。随着无线、植入式设备的发展，神经调节 治疗即将到来。这项研究的结果将为精确操控奠定必要的基础。 器官功能通过神经系统发挥作用，因此与 SPARC 计划的使命密切相关。

PROJECT SUMMARY The lung is a richly innervated organ. Strong evidence, including recent findings from us, demonstrates that neuronal control plays central roles in basic lung response to the environment, including immune activity, as well as airway and vascular smooth muscle tone which impacts air conductance and pulmonary blood pressure, respectively. However, the full extent of how the nervous system affects lung function remains unclear, and little is known of the anatomical and molecular features of the neurons that innervate the lung. Here, we propose to use cutting-edge viral-based circuit tracing, single cell transcriptomic and haploid ES cell- based genome editing technologies to: 1) label lung-innervating neurons; 2) determine their localization and projection pattern; 3) generate knockin mouse lines that will lay the foundation for neuromodulation of lung function. Findings generated in mice will be tested in human biopsy samples to delineate conserved versus species-specific mechanisms. With the development of wireless, implantable devices, neuromodulatory therapy is on the horizon. Findings from this study will lay the necessary foundation for precise manipulation of organ function through the nervous system, and thus closely comply with the mission of the SPARC program.