Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct

肝外胆管的损伤、进展和纤维化

基本信息

批准号：
10744500
负责人：
REBECCA G WELLS
金额：
$ 35.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744500
关键词：
Adult Affect Behavior Biliary Atresia Bilirubin Birth Cells Child Childhood Cicatrix Collagen Collagen Type I Data Deposition Development Diagnosis Disease Disease Progression Duct (organ) structure Early Diagnosis Equilibrium Event Extrahepatic Bile Ducts Fetus Fibroblasts Fibrosis Goals Growth Factor Hyaluronic Acid In Vitro Injury Interleukin-10 Intervention Liver Liver Cirrhosis Liver diseases Methods Molecular Weight Morbidity - disease rate Mothers Natural regeneration Nature Neonatal Newborn Infant Obstruction Oxidation-Reduction Perinatal Population Pregnancy Rare Diseases Recovery Reporting Role Stress Testing Therapeutic Tissues Work bile duct cholangiocyte fetal healing in utero in vivo injured liver transplantation neonate postnatal period prenatal programs regenerative repaired response response to injury therapeutic target therapy development wound wound healing

项目摘要

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.

项目摘要该建议的目的是确定胎儿与成人伤口愈合计划的作用 - 从一个是在出生左右发生的另一个 - 对胎儿/早期新生儿ep骨外胆管损伤的反应，例如在胆道闭锁（BA）中发生。 BA是全世界发生的一种罕见疾病，认为它是从产前环境侮辱 - 仅影响胎儿 - 对外ePARHEPATITIC胆管（EHBD）。婴儿出现出生时健康，但疾病迅速发展为纤维化和管道阻塞肝脏。有三个主要的未解决的问题融合了这一建议： 为什么EHBD在怀孕期间仅影响胎儿？ 一些患有胎儿EHBD损伤的婴儿是否恢复过来，如果是，为什么要恢复而不是纤维化？ 为什么出生后这种疾病会如此迅速？我们的初步数据表明，产前EHBD损伤导致最初的胎儿伤口愈合程序胎儿EHBD对受伤的反应。胎儿伤口愈合（已多次报道）结果在再生而不是疤痕中，对于高分子重量的沉积特别值得注意透明质酸（HA）而不是I型胶原蛋白，其生长因子环境包括IL-10而不是TGF-。从胎儿转变为成人伤口愈合程序的转变发生在妊娠后期。我们假设胎儿和成人伤口愈合程序按顺序确定对胎儿的反应 EHBD受伤；两者都有增强损害和伤害进展的潜力；那是选择这些反应将具有重大的治疗益处。我们建议通过2个特定的特定假设检验这些假设目的是研究从胎儿到新生儿序列的伤口愈合，包括出生应激的影响关于胎儿和成人之间的过渡计划：1）定义胎儿伤口愈合的性质及其影响关于胎儿EHBD的损伤反应； 2）确定与出生相关的压力和转换的影响在胎儿伤口愈合事件后，在载有HA的EHBD的背景下，成人伤口愈合程序。拟议中的工作将新概念（胎儿伤口愈合）引入了BA研究。了解胎儿 BA中的伤口愈合，其正面和负面影响在可能的发展中至关重要变革性治疗。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The heterogeneity of the biliary tree.

DOI：
10.1016/j.jhep.2021.04.016
发表时间：
2021-11
期刊：
JOURNAL OF HEPATOLOGY
影响因子：
25.7
作者：
de Jong, Iris E. M.;van den Heuvel, Marius C.;Walls, Rebecca G.;Porte, Robert J.
通讯作者：
Porte, Robert J.

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