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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

基本信息

批准号：
10516373
负责人：
Gianluca Cipriani
金额：
$ 40万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10516373
关键词：
3-Dimensional Address Adult Aging CSF1 gene Cells 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 Link Maintenance Mediating Microglia Molecular Molecular Profiling Mus Muscle Nerve Nerve Fibers Neuraxis Neuroglia Neurons PTPRC gene Patients Phenotype Population Population Distributions Population Heterogeneity RNA Regulation Research Role Signal Pathway Small Intestines Small intestine muscularis propria Synapses Testing Time Tissues Transgenic Mice Work base cell motility gastrointestinal gastrointestinal function macrophage migration monocyte mouse model neuron loss neuronal survival neurotransmission novel novel therapeutic intervention public health relevance recruit single-cell RNA sequencing synaptogenesis therapeutic target

项目摘要

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.

项目概要/摘要肠神经元（EN）需要通过调节神经传递来控制胃肠（GI）运动。损失 EN 的存在已在成人消化系统疾病和衰老过程中得到证实。在固有肌层胃肠道中，不同的巨噬细胞群，称为肌层巨噬细胞（MM），与正常的 EN 的开发和维护。虽然我们已经证明 MM 与 EN 密切相互作用，但分子可能调节 MMs-ENs 功能相互作用的因素尚不清楚。因此，使用 MM 作为调节目标 ENs在消化系统疾病中的作用，我们首先需要表征MMs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治疗消化系统疾病的新治疗策略。在为此应用生成的初步数据中，我们发现 (1) 一个新的人类 MM 群体与神经纤维有关。 (2) 从人类器官型中剔除这个新发现的 MM 群体小肠固有肌层培养物减少神经纤维。 (3) 慢病患者组织中的RNA 转运性便秘 (STC) 会减少补体 1qa (C1qa) 的表达，补体 1qa 是富含补体 1qa 的基因之一。新发现的MM群体。 (4) C1qa，新发现的人类中富集的基因之一 MM 群体仅由小鼠中的 MM 表达。 (5) 耗尽 MM 中的 C1qa 会减少突触标记物表达，改变胃肠道收缩性，并减少整个肠道转运时间。 (6) CSF1的条件性耗竭转基因小鼠模型中的 EN 会导致新发现的 MM、EN 和减少整个肠道的转运时间。因此，本申请的中心假设是表达 MM 的 C1qa 调节胃肠道神经传递，其表型取决于密切相关的 CSF1 释放 EN。在 SA1 中，我们计划描述 STC 患者中新发现的 MM 群体的特征，并评估其使用人类器官型培养物对胃肠道收缩性的贡献。在SA2中，我们计划研究这个的贡献新的 MM 群体对神经传递的影响。在 SA3 中，我们建议研究 EN 释放的 CSF1 对循环单核细胞的招募和分化为新的 MM 群体。从长远来看，我们预计这些研究将为将 MM 作为一种新型治疗方法奠定基础做出重大贡献在消化系统疾病（例如以 EN 丢失为特征的 STC）中调节 EN 的方法。