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Characterizing neurogenic progenitors in the adult intestine

成人肠道神经源性祖细胞的特征

基本信息

批准号：
9895033
负责人：
ALLAN M GOLDSTEIN
金额：
$ 36.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895033
关键词：
Ablation Adult Agonist Birth Cell Therapy Cells Chronic Clinical Colitis Colon Congenital Megacolon Constipation Coupled Data Digestive System Disorders Disease Distal Dominant-Negative Mutation Enteral Enteric Nervous System Epigenetic Process Esophageal achalasia Esthesia Excision Experimental Models Functional Gastrointestinal Disorders Functional disorder Gastroparesis Gene Expression Genetic Transcription Glial Differentiation Goals Health Human Hyperplasia Immunity In Vitro Injury Intestinal Pseudo-Obstruction Intestines Irritable Bowel Syndrome Knowledge Lead Life Mediating Methodology Modeling Morbidity - disease rate Mucositis Mus Mutation Nervous System Physiology Neuroglia Neurons Pathologic Pathway interactions Pharmacology Population Heterogeneity Process Regulation Reporter Rodent Role Serotonin Signal Pathway Signal Transduction Source Structure Subgroup Surface System Testing Transgenic Organisms absorption base cell motility density design experimental study gastrointestinal gastrointestinal function gastrointestinal infection genetic analysis improved in vitro Assay in vivo inflammatory disease of the intestine inhibitor/antagonist insight live cell imaging loss of function motility disorder mouse model nerve stem cell nervous system development neurogenesis novel strategies postnatal progenitor relating to nervous system response serotonin receptor single-cell RNA sequencing stem cell biology stem cells transcriptome transdifferentiation

项目摘要

Project Summary The enteric nervous system (ENS) is of fundamental importance to human health through its regulation of all aspects of gastrointestinal (GI) function, most notably gut motility. Congenital or acquired abnormalities of the ENS consequently can lead to serious functional GI disorders, including esophageal achalasia, gastroparesis, intestinal pseudo-obstruction, irritable bowel syndrome, Hirschsprung disease, and slow transit constipation. The adult intestine is known to possess neuronal progenitors, but their role and the mechanisms that activate them are unknown. We and others have observed the birth of new neurons in specific experimental injury models, including intestinal inflammation, GI infection, and following focal neuronal ablation. This neurogenic response can serve to replace neurons lost to injury, but it can also produce neuronal hyperplasia which can have significant pathologic consequences. Enteric neurogenesis is thus a double-edged sword that can be leveraged for a beneficial effect but needs to be modulated to limit its consequences. Our preliminary results suggest that experimental colitis in rodents promotes enteric glial cells to undergo a neurogenic transition via a 5-HT4-dependent pathway. However, this process is poorly understood. The overall objective of this proposal is to understand the mechanisms underlying postnatal enteric neurogenesis and its role in GI health and disease. To achieve this goal, we propose the following specific aims: (1) identify the downstream pathways that are activated by 5-HT4 signaling and lead to glial differentiation into neurons; (2) characterize the subpopulations of glial cells present in the intestine and determine the genetic and epigenetic changes that occur during the glia-to-neuron fate switch; and (3) leverage the intestine’s capacity for neurogenesis to treat the hypoganglionic transition zone associated with Hirschsprung disease. A variety of methodologies will be used to achieve these aims, including isolation and culture of enteric glia from reporter mice; in vitro assays using dominant-negative mutants and pharmacologic inhibitors to determine the signaling pathways involved in glial neurogenesis; single cell RNA seq to identify glial cell subpopulations; a dual reporter transgenic system for live cell imaging of glia-to-neuron cell fate transition; analysis of the genetic and epigenetic changes occurring during that transition; and induction of enteric neurogenesis in HSCR bowel to treat transition zone hypoganglionosis. Successful completion of these experiments will significantly enhance our understanding of the mechanisms underlying neurogenesis in the adult intestine, provide insights into the pathophysiology of neurointestinal diseases, identify new targets to modulate neurogenesis in vivo, offer novel approaches for expanding enteric neurons in the hypoganglionic transition zone of HSCR and in other neurointestinal diseases, and improve the in vitro expansion of enteric neuronal progenitors for cell therapy applications.

项目总结