CLEAR Consortium: Discovering the Developmental Mechanisms of Trachea-Esophageal Birth Defects

CLEAR联盟：发现气管-食管先天缺陷的发育机制

• 批准号: 10458157
• 负责人: Wendy K Chung
• 金额: $ 163.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458157
• 关键词: Academic Medical Centers; Address; Animal Model; Animals; Automobile Driving; Award; Bioinformatics; Birth; Breathing; Cells; Cellular biology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Congenital Abnormality; Congresses; Databases; Defect; Development; Diagnosis; Doctor of Philosophy; Educational workshop; Embryology; Esophageal Atresia; Esophagus; Etiology; Event; Fetal Development; Gene Mutation; Genes; Genetic; Genomics; Genotype; Goals; Human; In Vitro; Institution; Investigation; Life; Link; Magnetic Resonance Imaging; Methods; Mining; Modeling; Molecular; Morphogenesis; Mutation; Newborn Infant; Organoids; Paper; Patients; Pediatric Hospitals; Phenotype; Primitive foregut structure; Publishing; Registries; Research Personnel; Resources; Role; Scientist; Surgeon; Techniques; Technology; Testing; Tissue Engineering; Tissues; Trachea; Tracheoesophageal Fistula; Tube; United States National Institutes of Health; Variant; Xenopus; causal variant; clinical center; comorbidity; data integration; developmental genetics; embryo tissue; experience; feeding; genome sequencing; improved; innovation; mouse genetics; multidisciplinary; neonatal magnetic resonance imaging; novel; patient advocacy group; prevent; programs; repaired; risk variant; stem cells; success; synergism; web site

OVERALL | PROJECT SUMMARY The goal of the CLEAR Consortium is to elucidate the developmental and genetic mechanisms of trachea- esophageal birth defects (TEDs) to better understand their etiology, enhance diagnosis, improve treatment, and inform strategies to generate tissue in vitro that might ultimately be used for repair. The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Defects in trachea- esophageal development cause a spectrum of life-threatening TEDs, which occur in ~1:3500 births and prevent proper breathing and feeding in newborn infants. Gene mutations are known to cause TEDs but have only been identified in ~15% of cases and how these cause congenital malformations is poorly defined. To address this unmet need we have assembled an experienced and highly collaborative multi-disciplinary team of clinicians, surgeons, geneticists, computational scientists, and developmental and stem cell biologists that use an innovative combination of patient genome sequencing, neonatal MRI, animal models, quantitative cell biology, single cell genomics, CRISPR gene editing and human PSCs-derived organoids to study TEDs. This Multi-PI project centered at Cincinnati Children’s Hospital (CCHMC) and Columbia University Medical Center (CUMC) is led by Wendy Chung MD PhD (CUMC), Paul Kingma MD PhD (CCHMC), Yufeng Shen PhD (CUMC), James Wells PhD (CCHMC) and Aaron Zorn PhD (contact PI; CCHMC). Our program has 3 projects linked together by an Integrated Genomics Core. Project-1: Comprehensive phenotypic and genetic assessment of TED patients. Project-2: Defining the developmental mechanisms of TEDs in animal models. Project-3: Modeling EA in human PSC-derived embryonic tissues.

整体|项目摘要 CLEAR联盟的目标是阐明气管的发育和遗传机制， 食管出生缺陷（TEDs），以更好地了解其病因，提高诊断，改善治疗， 为在体外生成最终可能用于修复的组织提供了信息策略。气管和食管 在早期胎儿发育过程中，共同的前肠管分离而产生。气管缺陷- 食管发育引起一系列危及生命TED，发生率约为1：3500， 新生儿的正确呼吸和喂养。已知基因突变会导致TED，但目前为止 在约15%的病例中发现，这些疾病如何导致先天性畸形尚不清楚。为了解决这个 未满足的需求我们已经组建了一支经验丰富、高度协作的多学科临床医生团队， 外科医生，遗传学家，计算科学家，发育和干细胞生物学家， 患者基因组测序、新生儿MRI、动物模型、定量细胞生物学 单细胞基因组学、CRISPR基因编辑和人类PSC衍生的类器官来研究TED。这多PI 一个以辛辛那提儿童医院（CCHMC）和哥伦比亚大学医学中心（CAMC）为中心的项目， 由Wendy Chung MD PhD（CUMC）、Paul Kingma MD PhD（CCHMC）、Yufeng Shen PhD（CUMC）、James领导 威尔斯博士（CCHMC）和Aaron Zorn博士（联系PI; CCHMC）。我们的项目有三个项目， 整合基因组学核心 项目-1：TED患者的综合表型和遗传评估。 项目-2：在动物模型中定义TED的发育机制。 项目3：在人PSC衍生的胚胎组织中建模EA。