COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

先天性腹泻和肠病 (PediCODE) 联盟和 BioRepository

• 批准号: 10472774
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 171.5万
• 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/10472774
• 关键词: Advanced Development; Affect; Apoptosis; Applications Grants; Assimilations; 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; Epithelial; Epithelial Cells; 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; Life; Medical; 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; Postdoctoral Fellow; 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; data tools; endosome membrane; 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; protein transport; repository; screening; single-cell RNA sequencing; small molecule libraries; stool sample; technology development; therapeutic candidate; therapeutic gene; therapy development; 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： 本次拨款申请的目标是开发 PediCODE 联盟和生物储存库，并 确定先天性腹泻和肠病（CODE）的单基因原因。代码障碍很少见 单基因疾病的研究不足且与巨大的管理成本相关， 不良的终生结果。我们将描述这些疾病的临床和病理生理学特征 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储存库 主要患者材料。我们预计，通过这些努力，我们将鉴定出与 CODE，同时我们建立了独特的资源，可以对已知和未知的因果关系进行机制研究 代码基因。为了实现这些目标，我们组建了一个由医师科学家组成的多学科小组 对细胞生物学和导致腹泻的遗传性疾病有兴趣并有经验。 我们的目标将通过三个目标来实现。我们将首先开发一个前瞻性队列和注册表 受影响的 CODE 儿童并跟踪他们的临床病程。我们还将执行或收集整个外显子组的数据 对大多数这些患者进行测序，我们将开发一个 CODE 组织病理学图谱 活检样本。该联盟还将收集细胞样本（肠上皮、血液和皮肤成纤维细胞）， 以及血清和粪便样本。我们将研究从活检样本中产生的肠样物质， 和/或从多能干细胞生成肠道类器官，这些类器官将被表征和验证 通过免疫染色和 RNA 测序。然后，我们将利用现有技术并开发新技术 使用极化细胞、患者来源的细胞来表征和研究 CODE 疾病的上皮表型 肠类和疾病特异性斑马鱼模型。最后，我们将寻求描述功能变化的特征 我们的 CODE 患者队列中至少有 4 种新疾病。这种深入的分析将包括功能 使用肠道类器官进行表征，我们将评估屏障形成、活性离子和水 运输和囊泡运输/蛋白质分选。我们预计 PediCODE 联盟和 生物样本库将为患者及其家人、临床医生和实验室研究人员提供丰富的资源。我们 预计这些努力将扩大我们对 CODE 疾病的理解并确定新的方法 用于改善受影响儿童的临床症状。