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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：
10373979
负责人：
Faranak Fattahi
金额：
$ 35.37万
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/10373979
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 Neurons Neurosphere Neurotransmitters Nitrergic Neurons Nitric Oxide Nitric Oxide Synthase Type I Pathway interactions Patients Pattern Pharmacology Play Population Population Heterogeneity Process Production Regulation Reporting Research Role Smooth Muscle Spinal Stimulus Study models Surface Antigens System Therapeutic Intervention Time Tissues Transplantation base 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 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.

文摘