COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

项目总结/摘要： 该资助申请的目标是开发PediCODE联盟和生物储存库， 确定慢性腹泻和肠病（CODE）的单基因原因。CODE障碍是罕见的 单基因疾病，研究不足，并与巨大的管理成本， 不利的终身后果。我们将描述他们的临床和病理生理特征，这些 并开发疾病特异性细胞、组织和其他生物学资源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，我们将确定新的基因牵连， 代码，而我们建立了一个独特的资源，使机械研究已知和未知的因果关系， CODE基因。为了实现这些目标，我们组建了一个多学科的物理学家和科学家小组， 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。我们将首先开发一个前瞻性队列和登记研究， 受影响的CODE儿童，并遵循他们的临床过程。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（肠上皮细胞、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组织， 和/或从多能干细胞产生肠类器官，并且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新的技术， 使用极化细胞、患者源性细胞、细胞外基质细胞和细胞外基质细胞来表征和研究CODE病症的上皮表型。 肠道和疾病特异性斑马鱼模型。最后，我们将试图描述一个 我们的CODE患者队列中至少有4种新型疾病。这一深入分析将包括功能 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 生物储存库将为患者及其家属、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障碍的理解，并确定新的方法 用于改善受影响儿童的临床症状。

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.