Role of Muscularis Macrophages in the Enteric Nervous System

项目摘要/摘要 肠道神经元(Ens)通过调节神经传递来控制胃肠道(GI)运动。损失 ENS已被证实存在于成人的消化系统疾病和衰老过程中。在大脑的固有肌层中 在胃肠道，各种不同的巨噬细胞群，称为肌巨噬细胞(MMS)，与正常 ENS的开发和维护。虽然我们已经证明MMS与ENS密切相互作用，但分子 可能调节MMS-ENS功能相互作用的机制尚不清楚。因此，要把彩信作为规范的对象 在消化系统疾病中，我们首先需要确定人类MMS的表型并确定其机制 调节MMS-ENS的相互作用。我们的长期目标是确定调节MMS-ENS的信号通路 功能互动，并利用这些知识开发新的治疗策略来治疗消化系统疾病。 在为这一应用程序生成的初步数据中，我们发现(1)新的人类MMS种群 与神经纤维有关。(2)这个新发现的MMS群体从人类器官型中消失 培养的小肠固有肌会减少神经纤维。(3)慢性病患者组织中的RNA 传输性便秘(STC)降低了补体1QA(C1qA)的表达，补体1QA是一种富含在 新发现的彩信人群。(4)C1qa，新发现的人类富含的基因之一 MMS种群，是由MMS在小鼠体内唯一表达的。(5)从彩信中去除C1qa会减少突触 标记物的表达，改变胃肠收缩，并减少整个肠道通过时间。(6)有条件地耗尽CSF1 在转基因小鼠模型中从ENS中诱导新发现的MMS、ENS和 减少整个肠道的转运时间。因此，这一应用的中心假设是表达MMS的C1qA 调节胃肠道神经传递，其表型依赖于密切相关的CSF1释放 恩斯。在SA1中，我们计划描述STC患者中新发现的MMS人群的特征，并评估其 使用人体器官培养对胃肠道收缩能力的贡献。在SA2中，我们计划研究这方面的贡献 新的MMS人群对神经传递的影响。在SA3中，我们建议研究EN释放的CSF1在 循环单核细胞的募集和分化为MMS的新群体。从长远来看，我们 预计这些研究将为将MMS作为一种新的治疗方法奠定基础 在以ENS丢失为特征的消化系统疾病中调节ENS的方法，如STC。

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.