COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

先天性腹泻和肠病 (PediCODE) 联盟和 BioRepository

• 批准号: 10683735
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 169.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683735
• 关键词: Advanced Development; Affect; Apoptosis; Applications Grants; Atlases; Bioinformatics; Biological; Biological Assay; Biology; Biopsy Specimen; Blood; Bone Marrow Transplantation; Brush Border; Cell Polarity; Cell physiology; Cells; Cellular biology; Child; Clinical; Collecting Cell; Communities; DNA; DNA sequencing; Data; Defect; Diarrhea; Disease; Disease model; Endosomes; Epithelial Cells; Epithelium; FDA approved; Failure; Family; Feces; Fibroblasts; Foundations; Gastrointestinal Diseases; Genes; Genetic; Genetic Diseases; Genomics; Goals; Histopathology; Image; Infant; International; Intestinal Diseases; Intestines; Investigation; Ion Transport; Ions; Lead; Medical; Membrane; Mendelian disorder; Metadata; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Nutrient; Organoids; Outcome; Parents; Pathogenesis; Pathologic; Patients; Pediatric Hospitals; Phenotype; Physicians; Physiological; Physiology; Pluripotent Stem Cells; Prospective cohort; Protein Sortings; Proteins; Rare Diseases; Reagent; Registries; Research; Research Personnel; Resources; Sampling; Scientist; Serum; Signal Transduction; Skin; Specimen; Symptoms; Technology; Therapeutic; Tissues; Validation; Water; Zebrafish; absorption; base; biobank; clinical database; clinical development; cohort; congenital immunodeficiency; cost; exome sequencing; experience; gene function; high throughput screening; improved; induced pluripotent stem cell; interest; intestinal epithelium; member; mortality; multidisciplinary; new technology; next generation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; polarized cell; repository; screening; single-cell RNA sequencing; small molecule libraries; stool sample; technology development; therapeutic candidate; therapeutic gene; therapy development; tool; trafficking; transcriptome sequencing; Advanced Development; Affect; Apoptosis; Applications Grants; Atlases; Bioinformatics; Biological; Biological Assay; Biology; Biopsy Specimen; Blood; Bone Marrow Transplantation; Brush Border; Cell Polarity; Cell physiology; Cells; Cellular biology; Child; Clinical; Collecting Cell; Communities; DNA; DNA sequencing; Data; Defect; Diarrhea; Disease; Disease model; Endosomes; Epithelial Cells; Epithelium; FDA approved; Failure; Family; Feces; Fibroblasts; Foundations; Gastrointestinal Diseases; Genes; Genetic; Genetic Diseases; Genomics; Goals; Histopathology; Image; Infant; International; Intestinal Diseases; Intestines; Investigation; Ion Transport; Ions; Lead; Medical; Membrane; Mendelian disorder; Metadata; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Nutrient; Organoids; Outcome; Parents; Pathogenesis; Pathologic; Patients; Pediatric Hospitals; Phenotype; Physicians; Physiological; Physiology; Pluripotent Stem Cells; Prospective cohort; Protein Sortings; Proteins; Rare Diseases; Reagent; Registries; Research; Research Personnel; Resources; Sampling; Scientist; Serum; Signal Transduction; Skin; Specimen; Symptoms; Technology; Therapeutic; Tissues; Validation; Water; Zebrafish; absorption; base; biobank; clinical database; clinical development; cohort; congenital immunodeficiency; cost; exome sequencing; experience; gene function; high throughput screening; improved; induced pluripotent stem cell; interest; intestinal epithelium; member; mortality; multidisciplinary; new technology; next generation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; polarized cell; repository; screening; single-cell RNA sequencing; small molecule libraries; stool sample; technology development; therapeutic candidate; therapeutic gene; therapy development; tool; trafficking; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT: The goals of this grant application are to develop the PediCODE Consortium and Biorepository and to identify the monogenic causes of COngenital Diarrhea and Enteropathy (CODE). The CODE disorders are rare monogenic disorders that are under-researched and associated with an enormous management costs and adverse life-long outcomes. We will characterize their clinical and pathophysiological features of these disorders and develop a clinical database and biorepository of disease-specific cells, tissues, and other primary patient materials. We anticipate that through these efforts we will identify novel genes implicated in CODE, while we establish a unique resource enabling mechanistic studies on both known and unknown causal CODE genes. To achieve these goals, we have assembled a multidisciplinary group of Physician-Scientists that have interest and experience in cell biology and genetic disorders that result in diarrhea. Our goals will be accomplished with three aims. We will initially develop a prospective cohort and registry of affected CODE children and follow their clinical course. We will also perform or gather data of whole exome sequencing from the majority of these patients, and we will develop a CODE tissue histopathology atlas from biopsy samples. The consortium will also collect cell samples (intestinal epithelium, blood and skin fibroblasts), as well as serum and stool samples. We will investigate the enteroids generated from the biopsy samples, and/or generate intestinal organoids from pluripotent stem cells, and these will be characterized and validated by immunostaining and RNA sequencing. We will then utilize existing and develop novel technologies to characterize and investigate the epithelial phenotypes of CODE disorders using polarized cells, patient-derived enteroids and disease-specific zebrafish models. Finally, we will seek to characterize functional alterations in a minimum of 4 novel disorders from our cohort of CODE patients. This in-depth analysis will include functional characterization using intestinal organoids where we will assess barrier formation, active ion and water transport, and vesicular trafficking/protein sorting. We anticipate that the PediCODE Consortium and Biorepository will be a rich resource for patients and their families, clinicians and bench researchers. We anticipate that these efforts will expand our understanding of CODE disorders and identify novel approaches for improving clinical symptoms of affected children.

项目摘要/摘要： 该赠款申请的目标是开发脚踏码财团和生物座席，并 确定先天性腹泻和肠病（代码）的单基因原因。代码障碍很少见 研究不足并与巨大的管理成本相关的单基因疾病和 不利的终身结果。我们将表征它们的临床和病理生理特征 疾病并开发疾病特异性细胞，组织和其他疾病的临床数据库和生物座 主要的患者材料。我们预计，通过这些努力，我们将确定与 代码，我们建立了一个独特的资源，可以在已知和未知因果的情况下进行机械研究 代码基因。为了实现这些目标，我们组建了一个多学科的医师科学家组 在细胞生物学和遗传疾病中具有兴趣和经验，导致腹泻。 我们的目标将以三个目标来实现。我们最初将开发一个预期的队列和注册表 影响的代码孩子并遵循他们的临床课程。我们还将执行或收集整个外显子的数据 从大多数患者进行测序，我们将从 活检样品。财团还将收集细胞样品（肠上皮，血液和皮肤成纤维细胞）， 以及血清和粪便样品。我们将研究由活检样本产生的肠托素， 和/或从多能干细胞产生肠道类器官，这些细胞将被表征和验证 通过免疫染色和RNA测序。然后，我们将利用现有的并开发新技术 使用偏振细胞（患者衍生）表征和研究代码障碍的上皮表型 肠动物和疾病特异性斑马鱼模型。最后，我们将寻求表征一个功能变化 我们的代码患者队列中至少有4种新型疾病。深度分析将包括功能 使用肠道器官进行表征，我们将评估屏障形成，活性离子和水 运输和囊泡运输/蛋白质分类。我们预计子花园联盟和 生物座席将成为患者及其家人，临床医生和替补席研究人员的丰富资源。我们 预计这些努力将扩大我们对代码障碍的理解并确定新颖的方法 用于改善受影响儿童的临床症状。