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）是唯一拥有自己的肠神经系统的腹部器官 （ENS）完全包含在肠壁内，也称为肠道中的“第二大脑”，我们的长期目标是。 了解 ENS 中的内在初级感觉神经元 (IPAN) 如何检测和响应物理 和肠腔中的化学信号并控制结肠内容物的推进。 尽管 IPAN 已为人所知约 25 年，但它仍然是 ENS 中最神秘的神经元的一个子集 因为它们如何参与协调的肌肉运动（运动），调节免疫细胞功能 （免疫）和维持肠道屏障的完整性同样神秘。 IPAN能否发挥“模式发生器”的功能，控制周期的节奏？ 沿着结肠传播收缩主要是由于缺乏可选择性使用的工具。 操纵特定类别的肠神经元的兴奋性以及任何已尝试的药物 刺激或阻断 IPAN 的活性可能会作用于许多其他类型的神经元（或非神经元细胞）， 使得结果的解释不清楚。 在试点研究中，我们已经生成了关键资源，使我们能够识别并选择性地针对 β- 表达 CGRP（β-CGRP+）的 IPAN 通过使用这些独特的资源，我们将能够提出重要的问题。 关于 ENS 中 β-CGRP+ IPAN 的作用的问题： β-CGRP+ IPAN 在 ENS 中的作用是什么 神经活动沿着肠道传播？这些 IPAN 是否被机械和化学信号激活？ 这些 IPAN 可以作为不同微生物群衍生代谢物的细胞传感器吗？ 该提案代表了使用尖端神经遗传学方法的重大技术进步， 使基因靶向和确定 ENS 中 β-CGRP+ IPAN 的功能成为可能 离体和体内，首次深入了解 β-CGRP+ 如何选择性激活和抑制 ENS 中的 IPAN 影响 GI 运动。这些信息将增进我们对 GI 内部运作的理解。 ENS 并对开发治疗运动相关胃肠道的新策略提出了新见解 通过针对 ENS 中的 IPAN 来治疗疾病。