Identifying Gli-Regulated Targets during Tracheal Development and Disease

识别气管发育和疾病过程中 Gli 调节的靶点

基本信息

批准号：
9919618
负责人：
Talia S Nasr
金额：
$ 0.49万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-20 至 2020-06-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919618
关键词：
Address Bioinformatics Biological Process Cadherins Cartilage Cell Adhesion Cells Cellular biology Childhood Chondrogenesis Clinical Treatment Data Data Set Defect Development Diagnosis Disease Embryo Epithelial Epithelium Equilibrium Erinaceidae Esophagus Etiology Exhibits Extracellular Matrix FOXF1 gene Failure Fetal Development GLI3 gene Gene Expression Profiling Genes Genetic Genetic Predisposition to Disease Genomics Goals Human Impairment In Situ In Situ Hybridization In Vitro Lead Learning Lesion Literature Mediating Mesenchymal Mesenchymal Differentiation Mesenchyme Metalloproteases Modeling Molecular Morphogenesis Mus Mutation Online Mendelian Inheritance In Man Pallister-Hall syndrome Pathway interactions Patients Perinatal Physicians Prenatal Diagnosis Primitive foregut structure Process Proteins Publishing Research Review Literature Scientist Series Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Tissues Trachea Tracheal Atresia Tracheoesophageal Fistula Training Transgenic Organisms Tube WNT Signaling Pathway Xenopus base cartilage development causal variant clinical Diagnosis data mining exome sequencing experimental study fetal human tissue induced pluripotent stem cell loss of function mouse genetics mouse model mutant novel therapeutics overexpression programs respiratory smoothened signaling pathway transcription factor transcriptome sequencing treatment strategy virtual

项目摘要

Project Summary/Abstract This goal of this project is to identify the mechanisms by which Hedgehog/Gli signaling regulates tracheal development and how disruptions in this process can lead to perinatal tracheal defects. Errors in tracheal development may range from tracheal atresia and tracheoesophageal (TE) clefts, where the fetal foregut tube fails to separate properly, to tracheomalacia due to impaired tracheal chondrogenesis. The etiology of tracheal defects is poorly understood and new diagnoses and therapies are needed to address these relatively common yet potentially lethal defects. Human patient exome sequencing as well as murine mutant models have begun to identify a few developmental pathways that regulate tracheal development, including the Hedgehog/Gli pathway. For example, in murine models a total loss of Gli2 and Gli3 results in a complete failure of tracheal development, while some compound heterozygous Gli2;Gli3 mutants exhibit a TE cleft with tracheomalacia. In addition, our preliminary data suggests that transgenic expression of a Gli3 mutant that mimics the genetic lesion found in human Pallister-Hall syndrome patients also leads to impaired TE separation and virtually absent tracheal cartilage. The specific aims of this project are to identify Gli target genes in the developing trachea, to determine how Gli regulates TE separation and tracheal cartilage differentiation, and to model the mechanism of human tracheal defects. Preliminary RNA-seq studies of control and mutant foreguts have begun to define Gli targets during TE development. I will test the hypothesis that these candidate Gli target genes are misexpressed and/or mislocalized during TE development in Gli mutants. Our preliminary further data suggest that Wnt and BMP pathways act downstream of HH/Gli, and we will use a combination of mouse genetics and fetal foregut cultures to test the hypothesis that defective Wnt and BMP signaling is responsible for the defects in tracheal chondrogenesis. The results of these experiments will inform the basis of tracheal defects in human patients and as well as guide differentiation of tracheal iPSCs towards new therapeutic possibilities. This project will also provide valuable training in current clinical diagnosis and treatment strategies for these patients. !

项目概要/摘要该项目的目标是确定 Hedgehog/Gli 信号调节气管的机制发育以及该过程的中断如何导致围产期气管缺陷。气管错误发育可能包括气管闭锁和气管食管 (TE) 裂，其中胎儿前肠管未能正确分离，由于气管软骨形成受损而导致气管软化。气管炎的病因人们对这些缺陷知之甚少，需要新的诊断和疗法来解决这些相对常见的问题但潜在的致命缺陷。人类患者外显子组测序以及小鼠突变模型已经开始确定一些调节气管发育的发育途径，包括 Hedgehog/Gli 途径。例如，在小鼠模型中，Gli2 和 Gli3 的完全丧失会导致气管完全衰竭。发育，而一些复合杂合 Gli2;Gli3 突变体表现出 TE 裂并伴有气管软化。在此外，我们的初步数据表明，模仿遗传基因的 Gli3 突变体的转基因表达在人类 Pallister-Hall 综合征患者中发现的病变也会导致 TE 分离受损，并且实际上气管软骨缺失。该项目的具体目标是鉴定发育中气管中的 Gli 靶基因，以确定 Gli 如何调节 TE 分离和气管软骨分化，并模拟人类气管的机制缺陷。对照和突变前肠的初步 RNA-seq 研究已开始定义 Gli 靶标 TE 开发。我将检验以下假设：这些候选 Gli 靶基因表达错误和/或在 Gli 突变体的 TE 发育过程中错误定位。我们的初步进一步数据表明 Wnt 和 BMP 通路作用于 HH/Gli 下游，我们将结合小鼠遗传学和胎儿前肠培养物来检验 Wnt 和 BMP 信号传导缺陷导致气管缺陷的假设软骨形成。这些实验的结果将为人类患者气管缺陷的基础提供信息并指导气管 iPSC 向新的治疗可能性分化。该项目将还为这些患者提供有关当前临床诊断和治疗策略的宝贵培训。！