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COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

先天性腹泻和肠病 (PediCODE) 联盟和 BioRepository

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘: