COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

项目摘要/摘要： 这项赠款申请的目标是开发PediCODE联盟和生物库，并 确定先天性腹泻和肠病的单基因原因(代码)。密码障碍是罕见的。 单基因疾病研究不足，并与巨大的管理成本和 终生不良后果。我们将描述它们的临床和病理生理学特征。 并开发疾病特定细胞、组织和其他疾病的临床数据库和生物库 主要的病人材料。我们预计，通过这些努力，我们将发现与 代码，同时我们建立了一个独特的资源，能够对已知和未知的原因进行机械性研究 编码基因。为了实现这些目标，我们组建了一个由内科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疾病有兴趣和经验的人。 我们的目标将通过三个目标来实现。我们将初步制定一个预期的队列和登记 受影响的代码儿童，并遵循他们的临床进程。我们还将执行或收集整个外显子组的数据 从这些患者中的大多数进行测序，我们将从 活组织检查样本。该财团还将收集细胞样本(肠道上皮、血液和皮肤成纤维细胞)， 以及血清和粪便样本。我们将对活检样本产生的肠样进行调查， 和/或从多能干细胞产生肠道器官，这些将被表征和验证 通过免疫染色和RNA测序。然后，我们将利用现有的和开发的新技术来 使用患者来源的极化细胞表征和研究编码障碍的上皮表型 肠样体和疾病特异性斑马鱼模型。最后，我们将尝试描述一个 我们的CODE患者队列中至少有4种新的疾病。这一深入分析将包括功能 使用肠道有机物进行表征，我们将评估屏障形成、活性离子和水 运输，以及囊泡运输/蛋白质分选。我们预计PediCode联盟和 对于患者及其家人、临床医生和临床研究人员来说，生物信息库将是一个丰富的资源。我们 预计这些努力将扩大我们对代码障碍的理解，并确定新的方法 用于改善患病儿童的临床症状。

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.