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Human Enteroids, Colonoids, and iPSC derived HIO's to study CFTR-relatedDisorders

人类肠样、结肠样和 iPSC 衍生的 HIO 用于研究 CFTR 相关疾病

基本信息

批准号：
9551790
负责人：
Anjaparavanda P Naren
金额：
$ 10.24万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9551790
关键词：
Acceleration Address Affect Agonist Applications Grants Attenuated Biological Models Biopsy Cell Culture Techniques Cells Chronic Constipation Cyclic GMP Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Development Diarrhea Disease Exocrine pancreatic insufficiency FDA approved Fluids and Secretions Gastroenterologist Guanylate Cyclase Homeostasis Human Ileus Impairment Implant In Vitro Individual Intention Intestines Kidney Laboratories Liquid substance Lung Meconium Mediating Mesoderm Modeling Monitor Mus Mutation Organoids Pancreas Pathologic Pathology Patients Peptides Phenotype Physiological Population Proteins Pulmonary Function Test/Forced Expiratory Volume 1 Role Small Intestines Stem cells Testing Time Tissues assay development base capsule clinically relevant cystic fibrosis patients drug discovery enterotoxin receptor gain of function mutation gastrointestinal human disease human stem cells improved in vivo indexing induced pluripotent stem cell inhibitor/antagonist insight loss of function mutation multidisciplinary mutant patient subsets

项目摘要

PROJECT SUMMARY The unifying hypothesis to be tested in this proposal is that the mutant CFTR correcting and potentiating roles of guanylate cyclase 2C (GC-C)-agonists can restore fluid homeostasis of the gut in a subset of population with chronic constipation emanating from mutant CFTR functional deficit. We will test this hypothesis using patient derived intestinal stem cells derived from crypts (enteroids) to study fluid secretion in vitro; and the induced pluripotent stem cells (iPSCs) derived human intestinal organoids (HIOs) in mouse kidney capsule and be used as models to study fluid secretion in vivo. The proposed studies are highly significant because (i) it addresses the pathologies of several deadly human diseases by utilizing models from humans; (ii) it has clinical relevance and implications; (iii) it is a multidisciplinary project covers basic biomedical studies, assay developments, and drug discovery using personalized human stem cell cultures.

项目摘要在这个提议中要检验的统一假设是突变CFTR的纠正和增强作用鸟苷酸环化酶2C（GC-C）激动剂可以恢复肠道的液体稳态，源自突变CFTR功能缺陷的慢性便秘。我们将用病人来检验这个假设。来源于隐窝（肠样组织）的肠干细胞，以研究体外液体分泌; 多能干细胞（iPSC）衍生的人肠类器官（HIO）在小鼠肾被膜中，用作研究体内液体分泌的模型。这些研究非常重要，因为（i）通过利用人类模型解决了几种致命的人类疾病的病理学;（ii）它已经临床相关性和影响;（iii）它是一个多学科项目，涵盖基础生物医学研究，开发和药物发现使用个性化的人类干细胞培养。