Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct

项目摘要 该提案的目标是确定胎儿与成人伤口愈合计划的作用-以及从 一个发生在出生前后-在对胎儿/早期新生儿肝外胆管损伤的反应中， 例如发生在胆道闭锁（BA）中。BA是一种在世界范围内发生的罕见疾病，被认为是由 产前环境损伤-仅影响胎儿-肝外胆管（EHBD）。出生的宝宝似乎 出生时健康，但疾病迅速进展为纤维化、导管阻塞和肝硬化 肝脏的有三个主要的未回答的问题促使这项建议： 为什么怀孕期间的EHBD损伤只影响胎儿？ 一些患有胎儿EHBD损伤的婴儿会恢复吗？如果是的话，为什么会恢复而不是纤维化？ 为什么出生后病情发展如此之快？ 我们的初步数据表明，产前EHBD损伤导致的程序，胎儿伤口愈合的最初阶段， 胎儿EHBD对损伤的反应。胎儿伤口愈合，这已被报道在多个组织，结果 在再生而不是结疤，是特别值得注意的高分子量的沉积 透明质酸（HA）而不是I型胶原，具有包括IL-10而不是TGF-β的生长因子环境。 从胎儿伤口愈合程序到成人伤口愈合程序的转换发生在妊娠后期。 我们假设胎儿和成人的伤口愈合程序，在顺序上，决定了对胎儿的反应。 EHBD损伤;两者都有可能增加损伤和损伤进展;并且选择这些 反应将具有主要的治疗益处。我们建议通过两个具体的假设来测试这些假设。 旨在研究从胎儿到新生儿的伤口愈合，包括纳塔尔压力的影响。 关于胎儿和成人之间的过渡程序：1）定义胎儿伤口愈合的性质及其影响 对胎儿EHBD损伤反应的影响; 2）确定出生相关应激的影响和转换 在胎儿伤口愈合事件后，在HA负载的EHBD的背景下的成人伤口愈合程序。 拟议的工作引入了一个新的概念-胎儿伤口愈合-BA的研究。了解胎儿 BA中的伤口愈合，无论是积极的还是消极的影响，在潜在的发展中都是必不可少的。 变革性治疗

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.