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.

项目总结/摘要 肠神经元（EN）通过调节神经传递来控制胃肠（GI）运动。损失 在成人和老年人的消化系统疾病中已经证实了EN的存在。在固有肌层中， 在胃肠道中，各种各样的巨噬细胞，称为肌层巨噬细胞（muscularis macrophages，简称MMCs），与正常的胃肠道细胞有联系。 虽然我们已经表明，ENS密切相互作用的EN，分子 可能调节MMs-EN功能相互作用的机制尚不清楚。因此，将碳纳米管作为调控目标， 在消化系统疾病中，我们首先需要描述ENS在人类中的表型并确定其机制 调节MMs-ENs相互作用。我们的长期目标是确定调节MMs-ENs的信号通路 功能相互作用，并利用这些知识开发新的治疗策略来治疗消化系统疾病。 在为该应用程序生成的初步数据中，我们发现（1）一个新的人类种群， 与神经纤维有关。(2)从人类器官型中消耗这种新发现的哺乳动物种群 小肠固有肌层的培养物减少了神经纤维。(3)来自慢性胰腺炎患者组织的RNA 转运性便秘（STC）的补体1 qa（C1 qa）表达减少，补体1 qa是富含 新发现的黑猩猩种群(4)C1 qa是新发现的人类基因中富集的基因之一， 在小鼠中仅由β-内酰胺酶表达。(5)消耗C1 qa减少突触 标志物表达，改变GI收缩性并减少全肠通过时间。(6)CSF 1的条件性耗竭 在转基因小鼠模型中从EN中诱导新发现的ESTs、EN和 减少整个肠道的运输时间。因此，本申请的中心假设是表达C1 qa的C1 qa是一种表达C1 qa的细胞。 调节GI神经传递，其表型依赖于CSF 1从密切相关的 少尉在SA 1中，我们计划描述STC患者中新发现的ESTA人群的特征，并评估其 使用人器官型培养物对GI收缩性的贡献。在SA 2中，我们计划研究这种 神经传递的新的群体。在SA 3中，我们建议研究EN释放的CSF 1对 循环单核细胞的募集和分化为新的单核细胞群。从长远来看，我们 我希望这些研究将为靶向治疗作为一种新的治疗方法奠定基础 在消化系统疾病中调节EN的方法，例如STC，其特征在于EN的丧失。