Role of Muscularis Macrophages in the Enteric Nervous System

肌层巨噬细胞在肠神经系统中的作用

• 批准号: 10688056
• 负责人: Gianluca Cipriani
• 金额: $ 40万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688056
• 关键词: 3-Dimensional; Adult; Aging; CSF1 gene; Cells; Central Nervous System; Coculture Techniques; Colon; Communication; Complement; Constipation; Data; Development; Digestive System Disorders; Electron Microscopy; Enteral; Enteric Nervous System; Face; Gastrointestinal Motility; Gastrointestinal Physiology; Gastrointestinal tract structure; Gene Expression; Genes; Goals; Human; Immune; Immunohistochemistry; Knowledge; Knowledge acquisition; Link; Macrophage; Maintenance; Mediating; Microglia; Molecular; Molecular Profiling; Mus; Muscle; Nerve; Nerve Fibers; Neuroglia; Neurons; PTPRC gene; Patients; Phenotype; Population; Population Distributions; Population Heterogeneity; RNA; Regulation; Research; Role; Signal Pathway; Small Intestines; Small intestine muscularis propria; Sorting; Synapses; Testing; Time; Tissues; Transgenic Mice; Work; cell motility; gastrointestinal; gastrointestinal function; migration; monocyte; mouse model; neuron loss; neuronal survival; neurotransmission; novel; novel therapeutic intervention; public health relevance; recruit; single-cell RNA sequencing; synaptogenesis; therapeutic target

PROJECT SUMMARY/ABSTRACT Enteric neurons (ENs) are required to control gastrointestinal (GI) motility by regulating neurotransmission. Loss of ENs has been demonstrated in digestive diseases in adults and during aging. In the muscularis propria of the GI tract, diverse populations of macrophages, called muscularis macrophages (MMs), are linked to the normal development and maintenance of ENs. While we have shown that MMs closely interact with ENs, the molecules that may regulate MMs-ENs functional interactions are unknown. Thus, to use MMs as a target for regulating ENs in digestive diseases, we first need to characterize MMs’ phenotype in humans and identify the mechanisms regulating MMs-ENs interaction. Our long-term goal is to determine the signaling pathways regulating MMs-ENs functional interaction and use this knowledge to develop new therapeutic strategies to treat digestive diseases. In preliminary data generated for this application, we discovered (1) a new population of human MMs closely associated with nerve fibers. (2) Depletion of this newly discovered MMs population from human organotypic cultures of small intestine muscularis propria reduces nerve fibers. (3) RNAs from tissues of patients with slow transit constipation (STC) have reduced expression of Complement 1qa (C1qa), one of the genes enriched in the newly discovered population of MMs. (4) C1qa, one of the genes enriched in the newly discovered human MMs population, is exclusively expressed by MMs in mice. (5) Depleting C1qa from MMs reduces synaptic marker expression, alters GI contractility, and reduces whole gut transit time. (6) Conditional depletion of CSF1 from ENs in a transgenic mouse model induces loss of the newly discovered population of MMs, ENs and reduces whole gut transit time. Thus, the central hypothesis of this application is that C1qa expressing MMs regulate GI neurotransmission, and their phenotype depends on CSF1 released from closely associated ENs. In SA1, we plan to characterize this newly discovered MMs population in STC patients and assess its contribution to GI contractility using human organotypic cultures. In SA2, we plan to study the contribution of this novel population of MMs to neurotransmission. In SA3, we propose to study the role of EN-released CSF1 on circulating monocytes’ recruitment and differentiation into the novel population of MMs. In the long term, we expect these studies will contribute substantially to creating the basis for targeting MMs as a novel therapeutic approach to regulate ENs in digestive diseases, such as STC, characterized by loss of ENs.

项目摘要/摘要 肠神经元（ENS）需要通过控制神经传递来控制胃肠道（GI）运动。损失 在成人和衰老期间的消化疾病中已经证明了ENS的ENS。在Muscularis of the of 胃肠道，巨噬细胞的潜水种群，称为巨噬细胞（MMS），与正常 ENS的开发和维护。虽然我们已经证明MMS与ENS紧密相互作用，但分子是 这可能调节MMS-GEN功能相互作用是未知的。这是将MMS作为确定的目标 在消化疾病中，我们首先需要表征MMS的表型并确定机制 调节MMS-INS相互作用。我们的长期目标是确定调节MMS的信号通路 功能相互作用并利用这些知识来开发新的治疗策略来治疗消化系统疾病。 在本应用程序生成的初步数据中，我们发现了（1）新的人类MMS人群 与神经纤维相关。 （2）从人体器官中耗尽了这种新发现的MMS人群 小肠肌肉的培养物降低了神经纤维。 （3）慢速患者组织的RNA 过境便秘（STC）的补体1QA（C1QA）的表达降低，这是富含的基因之一 新发现的MMS人口。 （4）C1QA，富含新发现的人的基因之一 MMS种群由MMS在小鼠中专门表达。 （5）从MMS耗尽C1QA，还原突触 标记表达，改变GI的收缩力并减少整个肠道传输时间。 （6）CSF1的条件耗竭 从转基因小鼠模型中的ENS引起新发现的MMS，ENS和 减少整个肠道运输时间。这是此应用的中心假设是表达MMS的C1QA 调节GI神经传递，其表型取决于密切相关的CSF1 ens。在SA1中，我们计划在STC患者中表征这种新发现的MMS人群并评估其 使用人体器官培养物对胃肠道收缩的贡献。在SA2中，我们计划研究这一点的贡献 神经传递的新型MMS人群。在SA3中，我们建议研究收到的CSF1在 循环单核细胞的招募和分化为新的MMS人群。从长远来看，我们 期望这些研究将为靶向MMS作为一种新疗法的基础做出重大贡献 调节消化疾病（例如STC）中ENS的方法，其特征是ENS的丧失。