Grant: CIHR Fellowship

Trachea-esophageal birth defects (TEDs) occur when the trachea and esophagus do not completely separate from a common gut tube during fetal development. Occurring in about one out of every 3,000 live births, these life-threatening birth defects prevent proper breathing or feeding in newborn infants. It is not yet well understood how these birth defects happen. There is compelling evidence of a genetic cause, but specific genetic mutations are only known in 15% of TED cases worldwide, moreover it is unclear how these mutations disrupt fetal development. The goal of my research project is to determine the genetic and cellular causes of TEDs using an innovative combination of animal models and bioengineered human esophageal tissue from patient stem cells. As part of CLEARconsortium.org, our human geneticist colleagues have found a number of genetic variations (mutations) from genome sequencing over 300 TED patients, but we do not know which mutations cause disease. My goal is to identity the causative mutations and investigate how they cause TEDs. By making similar mutations in frogs and mouse embryos I have screened over 20 variants and found several that cause defects similar to patients, and thus are likely to be causative, including the gene ITSN1. Excitingly this has revealed a novel cellular pathway known as endosome-mediated epithelial remodeling. I propose to 1) continue screening patient variants, 2) determine the molecular mechanism by which ITSN1 regulates trachea-esophageal development and 3) test the hypothesis that other genes in this pathway may be disrupted in patients. My proposed research will discover the origin of TEDs, which will provide new fundamental knowledge of the genetic and cellular networks regulating normal and disrupted trachea-esophageal development, ultimately improving the diagnosis and treatment of children born with these life-threatening conditions.