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:
- 金额:$ 36.33万
- 依托单位:
- 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:
- 关键词:AblationAdultAgonistBirthCell TherapyCellsChronicClinicalColitisColonCongenital MegacolonConstipationCoupledDataDigestive System DisordersDiseaseDistalDominant-Negative MutationEnteralEnteric Nervous SystemEpigenetic ProcessEsophageal achalasiaEsthesiaExcisionExperimental ModelsFunctional Gastrointestinal DisordersFunctional disorderGastroparesisGene ExpressionGenetic TranscriptionGlial DifferentiationGoalsHealthHumanHyperplasiaImmunityIn VitroInjuryIntestinal Pseudo-ObstructionIntestinesIrritable Bowel SyndromeKnowledgeLeadLifeMediatingMethodologyModelingMorbidity - disease rateMucositisMusMutationNervous System PhysiologyNeurogliaNeuronsPathologicPathway interactionsPharmacologyPopulation HeterogeneityProcessRegulationReporterRodentRoleSerotoninSignal PathwaySignal TransductionSourceStructureSubgroupSurfaceSystemTestingTransgenic Organismsabsorptionbasecell motilitydensitydesignexperimental studygastrointestinalgastrointestinal functiongastrointestinal infectiongenetic analysisimprovedin vitro Assayin vivoinflammatory disease of the intestineinhibitor/antagonistinsightlive cell imagingloss of functionmotility disordermouse modelnerve stem cellnervous system developmentneurogenesisnovel strategiespostnatalprogenitorrelating to nervous systemresponseserotonin receptorsingle-cell RNA sequencingstem cell biologystem cellstranscriptometransdifferentiation
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ALLAN M GOLDSTEIN其他文献
ALLAN M GOLDSTEIN的其他文献
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{{ truncateString('ALLAN M GOLDSTEIN', 18)}}的其他基金
Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease.
揭示脂肪组织来源的神经干细胞治疗先天性巨结肠的潜力。
- 批准号:
10580052 - 财政年份:2022
- 资助金额:
$ 36.33万 - 项目类别:
Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease.
揭示脂肪组织来源的神经干细胞治疗先天性巨结肠的潜力。
- 批准号:
10452149 - 财政年份:2022
- 资助金额:
$ 36.33万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10066349 - 财政年份:2020
- 资助金额:
$ 36.33万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10319974 - 财政年份:2020
- 资助金额:
$ 36.33万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10545000 - 财政年份:2020
- 资助金额:
$ 36.33万 - 项目类别:
Development of the Enteric Nervous System: Cells, Signals, Genes, and Therapy
肠神经系统的发育:细胞、信号、基因和治疗
- 批准号:
9541099 - 财政年份:2018
- 资助金额:
$ 36.33万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8464065 - 财政年份:2009
- 资助金额:
$ 36.33万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8277360 - 财政年份:2009
- 资助金额:
$ 36.33万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠神经系统发育
- 批准号:
7730368 - 财政年份:2009
- 资助金额:
$ 36.33万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8072025 - 财政年份:2009
- 资助金额:
$ 36.33万 - 项目类别:
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