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Human pluripotent stem cells for the study of gastrointestinal dysmotility

人类多能干细胞用于胃肠动力障碍研究

基本信息

批准号：
10609875
负责人：
Faranak Fattahi
金额：
$ 34.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609875
关键词：
Adult Affect Behavior Brain Cell Therapy Cell model Cells Chemicals Complex Congenital Megacolon Cues Defect Derivation procedure Development Disease Disease model Dissection Engraftment Enteral Enteric Nervous System Enzymes Esophageal achalasia Experimental Models Functional disorder Gastrointestinal Motility Gastroparesis Goals Human Hypertrophic Pyloric Stenosis Intestinal Motility Investigation Knockout Mice Link Maps Medical Modeling Motor Neurons Mus Muscle Neuronal Differentiation Neurons Neurosphere Neurotransmitters Nitrergic Neurons Nitric Oxide Nitric Oxide Synthase Type I Pathway interactions Patients Pattern Play Population Population Heterogeneity Process Production Regulation Relaxation Reporting Research Role Smooth Muscle Specific qualifier value Spinal Cord Stimulus Study models Surface Antigens System Therapeutic Intervention Time Tissues Transplantation cell motility cell replacement therapy cell type clinical phenotype drug discovery enteric neuropathy follow-up gastrointestinal human pluripotent stem cell in vitro Model infancy inhibitory neuron innovation motility disorder mouse model nervous system disorder neuron component pharmacologic prospective reconstruction regeneration potential regenerative response screening small molecule stem cell differentiation therapeutically effective transcriptomics treatment strategy

项目摘要

Abstract The enteric nervous system (ENS) accomplishes a broad range of activities that rely on a remarkably diverse population of neuronal and glial subtypes. Loss of specific cell types, such as nitric oxide (NO) producing neurons (nitrergic neurons) leads to enteric neuropathies associated with dysmotility disorders including esophageal achalasia, gastroparesis and infantile hypertrophic pyloric stenosis. The underlying pathophysiology of these disorders have remained largely unknown due to limitations of currently available cellular models. We have recently reported a new alternative approach for differentiation of ENS lineages from human pluripotent stem cells under fully defined conditions, providing a unique and reliable framework for ENS disease modeling and drug discovery. Taking advantage of high content chemical compound screening in combination with fate map reconstruction guided by single cell transcriptomics, here we propose a new strategy for efficient derivation and prospective isolation of enteric nitrergic neurons. This system will provide a unique in vitro model for identification of pharmacological regulator of these neurons and dissection of cellular mechanisms that underlie GI dysmotilty. We will further evaluate the potential of these neurons in transplantation studies aimed at the ultimate development of cell-based treatment of enteric neuropathies related to the loss of nitrergic neurons.

摘要肠神经系统（ENS）完成广泛的活动，这些活动依赖于一个显着的神经元和神经胶质细胞亚型的多样性。特定细胞类型的丢失，如一氧化氮（NO）产生神经元（氮能神经元）导致与运动障碍相关的肠神经病这些疾病包括食管失弛缓症、胃轻瘫和婴儿肥厚性幽门狭窄。这些疾病的潜在病理生理学由于研究的局限性，目前可用的细胞模型。我们最近报道了一种新的替代方法，在完全确定的条件下从人多能干细胞分化ENS谱系，为ENS疾病建模和药物发现提供了独特而可靠的框架。高含量化合物筛选与命运图重建相结合的优势在单细胞转录组学的指导下，我们提出了一种新的有效衍生策略，该系统将为肠氮能神经元的分离提供一个独特的体外模型，这些神经元药理学调节剂的鉴定和细胞机制的剖析，我们将进一步评估这些神经元在移植研究中的潜力目的是最终开发基于细胞的治疗肠神经病的方法，氮能神经元。