Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits

肠神经回路中内在感觉神经元功能的遗传分析

• 批准号: 10568622
• 负责人: Hongzhen Hu
• 金额: $ 55.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10568622
• 关键词: Abdomen; Ablation; Address; Affect; Afferent Neurons; Animals; Biological Assay; Biology; Brain; Calcitonin Gene-Related Peptide; Cell physiology; Cells; Chemicals; Colon; Communication; Complex; Cues; Defect; Development; Enteral; Enteric Nervous System; Enteroendocrine Cell; Environment; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Genetic; Goals; Health; Image; Immune; Immunity; Intestines; Mechanical Stimulation; Mechanics; Mediating; Medical; Modeling; Molecular; Movement; Mucous Membrane; Mus; Muscle; Nerve; Nerve Endings; Nervous System; Neuroglia; Neuromodulator; Neurons; Neuropeptides; Organ; Patients; Pattern; Periodicity; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Pilot Projects; Play; Preparation; Productivity; Quality of life; Resources; Role; Sensory; Signal Transduction; Stimulus; Technology; Testing; Translating; Vertebrates; cell motility; cholinergic; detection platform; gain of function; gastrointestinal; gastrointestinal function; genetic analysis; genetic approach; genetic manipulation; gut microbiome; gut microbiota; gut-brain axis; in vivo; insight; intestinal barrier; intestinal homeostasis; loss of function; microbiota metabolites; motility disorder; motor behavior; nervous system disorder; neural; neural circuit; neurogenetics; new therapeutic target; novel strategies; optogenetics; response; sensor; tool; treatment strategy

SUMMARY The gastrointestinal (GI) tract is the only abdominal organ that has evolved with its own enteric nervous system (ENS) fully contained within the gut wall, also known as the “second brain” in the gut. Our long-term goal is to understand how the intrinsic primary sensory neurons (IPANs) in the ENS detect and respond to both physical and chemical cues in the gut lumen and control propulsion of content in the colon. Although known for about 25 years, the IPANs are still a subset of the most mysterious neurons in the ENS because how they participate in coordinated muscle movements (motility), regulate immune cell function (immunity) and maintain integrity of intestinal barrier is not completely understood. Equally as mysterious is whether the IPANs can fulfil the function as a “pattern generator” and can control the rhythmicity of cyclical propagating contractions along the colon. This is largely due to a lack of tools that can be used to selectively manipulate the excitability of specific classes of enteric neurons and any drugs that have been tried to stimulate or block activity in IPANs will likely act on many other types of neurons (or non-neuronal cells), making interpretation of the results unclear. In pilot studies, we have generated critical resources enabling us to identify and selectively targeting the β- CGRP-expressing (β-CGRP+) IPANs. By using these unique resources, we will be able to ask important questions regarding the roles of the β-CGRP+ IPANs in the ENS: What role the β-CGRP+ IPANs have in the propagation of neural activity along the gut? Are these IPANs activated by both mechanical and chemical cues in the gut lumen? Can these IPANs serve as cellular sensors for distinct microbiota-derived metabolites? This proposal represents a major technical advance by using cutting-edge neurogenetic approaches which make it possible to genetically target and determine the functionality of the β-CGRP+ IPANs in the ENS both ex vivo and in vivo, providing the first insights into how selective activation and inhibition of the β-CGRP+ IPANs in the ENS affects GI-motility. This information will advance our understanding of the inner workings of the ENS and shed new insights on the development of novel strategies for the treatment of motility-related GI disorders by targeting the IPANs in the ENS.

概括 胃肠道（GI）道是唯一随着其肠神经系统进化的腹部器官 （ENS）完全包含在肠壁中，也称为肠道中的“第二脑”。我们的长期目标是 了解ENS中的固有主要感觉神经元（IPAN）如何检测并响应这两种物理 和肠道内的化学提示，并控制结肠中含量的推进。 尽管IPAN大约25年，但IPAN仍然是ENS中最神秘的神经元的子集 因为他们如何参与协调的肌肉运动（运动），调节免疫细胞功能 （免疫力）并保持肠道屏障的完整性尚未完全理解。同样神秘的是 IPAN是否可以作为“模式发生器”来实现该功能，并且可以控制周期性的节奏性 沿结肠传播宫缩。这主要是由于缺乏可用于选择性的工具 操纵特定类别的肠神经元和任何试图尝试的药物的兴奋 刺激或阻断IPAN的活性可能会对许多其他类型的神经元（或非神经元细胞）作用， 使结果解释不清楚。 在试点研究中，我们产生了关键的资源，使我们能够识别并有选择地靶向β- CGRP表达（β-CGRP+）IPAN。通过使用这些独特的资源，我们将能够问重要 有关β-CGRP+ ipans在ENS中的作用的问题：β-CGRP+ IPAN在 沿肠道的神经活动的传播？这些IPAN是否被机械和化学提示激活 在肠道里？这些IPAN可以用作不同微生物源代谢物的细胞传感器吗？ 该提案通过使用尖端的神经遗传学方法代表了一个重大的技术进步 使得可以普遍靶向并确定ENS中β-CGRP+ IPAN的功能 离体和体内，提供了对β-CGRP+选择性激活和抑制的首次见解 ENS中的IPAN会影响胃肠道。这些信息将提高我们对内在运作的理解 ENS并提供了有关与运动相关的GI治疗新策略发展的新见解 通过针对ENS中的IPAN来定位疾病。