PROJECT SUMMARY The goal of this proposal is to determine the role of fetal vs. adult wound healing programs – and the switch from one to the other that occurs around birth – in the response to fetal/early neonatal extrahepatic bile duct injury, such as occurs in biliary atresia (BA). BA is a rare disease occurring worldwide that it is thought to occur from a prenatal environmental insult – affecting only the fetus – to the extrahepatic bile duct (EHBD). Babies appear healthy at birth, but undergo rapid progression of the disease to fibrosis and obstruction of the duct and cirrhosis of the liver. There are three major unanswered questions that motivate this proposal: Why does an EHBD insult during pregnancy affect only the fetus? Do some babies with fetal EHBD injury recover, and if yes, why recovery rather than fibrosis? Why does the disease progress so rapidly after birth? Our preliminary data suggest that prenatal EHBD injury leads to a program of fetal wound healing in the initial response of the fetal EHBD to injury. Fetal wound healing, which has been reported in multiple tissues, results in regeneration rather than scarring and is particularly notable for the deposition of high molecular weight hyaluronic acid (HA) rather than type I collagen, with a growth factor milieu that includes IL-10 rather than TGF-. The switch from a fetal to an adult wound healing program occurs late in gestation. We hypothesize that fetal and adult wound healing programs, in sequence, determine the response to fetal EHBD injury; that both have the potential to enhance damage and injury progression; and that co-opting these responses would have a major therapeutic benefit. We propose to test these hypotheses through 2 specific aims that study wound healing in sequence from the fetus to the newborn, including the impact of natal stress on the transitional program between fetal and adult: 1) Define the nature of fetal wound healing and its impact on the injury response in the fetal EHBD; and 2) Determine the impact of birth-associated stress and the switch to an adult wound healing program in the context of an HA-laden EHBD after the events of fetal wound healing. The proposed work introduces a new concept – fetal wound healing – to the study of BA. Understanding fetal wound healing in BA, both its positive and negative effects, will be essential in the development of potentially transformative treatments.