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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：
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
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/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

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.

项目总结/文摘