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人及斑马鱼胎儿生长受限模型中Wnt/β-连环蛋白和Jak/Stat3信号通路的过度激活：对药物挽救的启示

Hyperactivation of Wnt/β-catenin and Jak/Stat3 pathways in human and zebrafish foetal growth restriction models: Implications for pharmacological rescue.

作者信息

Risato Giovanni, Celeghin Rudy, Brañas Casas Raquel, Dinarello Alberto, Zuppardo Alessandro, Vettori Andrea, Pilichou Kalliopi, Thiene Gaetano, Basso Cristina, Argenton Francesco, Visentin Silvia, Cosmi Erich, Tiso Natascia, Beffagna Giorgia

机构信息

Department of Biology, University of Padova, Padova, Italy.

Department of Cardio-Thoraco-Vascular Sciences and Public Health, University of Padova, Padova, Italy.

出版信息

Front Cell Dev Biol. 2022 Aug 16;10:943127. doi: 10.3389/fcell.2022.943127. eCollection 2022.

DOI:10.3389/fcell.2022.943127
PMID:36051436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9424487/
Abstract

Foetal Growth Restriction (FGR), previously known as Intrauterine Growth Restriction (IUGR), is an obstetrical condition due to placental insufficiency, affecting yearly about 30 million newborns worldwide. In this work, we aimed to identify and pharmacologically target signalling pathways specifically involved in the FGR condition, focusing on FGR-related cardiovascular phenotypes. The transcriptional profile of human umbilical cords from FGR and control cases was compared with the response to hypoxia of zebrafish () transgenic lines reporting the activity of twelve signalling pathways involved in embryonic development. Wnt/β-catenin and Jak/Stat3 were found as key pathways significantly dysregulated in both human and zebrafish samples. This information was used in a chemical-genetic analysis to test drugs targeting Wnt/β-catenin and Jak/Stat3 pathways to rescue a set of FGR phenotypes, including growth restriction and cardiovascular modifications. Treatments with the Wnt/β-catenin agonist SB216763 successfully rescued body dimensions, cardiac shape, and vessel organization in zebrafish FGR models. Our data support the Wnt/β-catenin pathway as a key FGR marker and a promising target for pharmacological intervention in the FGR condition.

摘要

胎儿生长受限（FGR），以前称为宫内生长受限（IUGR），是一种由于胎盘功能不全引起的产科病症，全球每年约有3000万新生儿受其影响。在这项研究中，我们旨在识别并从药理学角度靶向与FGR病症特别相关的信号通路，重点关注与FGR相关的心血管表型。将FGR病例和对照病例的人脐带转录谱与斑马鱼转基因品系对缺氧的反应进行比较，这些品系报告了参与胚胎发育的12条信号通路的活性。发现Wnt/β-连环蛋白和Jak/Stat3是在人类和斑马鱼样本中均显著失调的关键通路。该信息被用于化学遗传学分析，以测试靶向Wnt/β-连环蛋白和Jak/Stat3通路的药物，以挽救一系列FGR表型，包括生长受限和心血管改变。用Wnt/β-连环蛋白激动剂SB216763治疗成功挽救了斑马鱼FGR模型中的身体尺寸、心脏形状和血管组织。我们的数据支持Wnt/β-连环蛋白通路作为关键的FGR标志物以及FGR病症药物干预的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/87dd0b0da113/fcell-10-943127-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/690f068a46ce/fcell-10-943127-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/40c48f1576a5/fcell-10-943127-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/8afc088e3686/fcell-10-943127-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/14c74241aba1/fcell-10-943127-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/8b1c08009cd6/fcell-10-943127-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/9c90bc9baa09/fcell-10-943127-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/87dd0b0da113/fcell-10-943127-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/690f068a46ce/fcell-10-943127-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/40c48f1576a5/fcell-10-943127-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/8afc088e3686/fcell-10-943127-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/14c74241aba1/fcell-10-943127-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/8b1c08009cd6/fcell-10-943127-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/9c90bc9baa09/fcell-10-943127-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a2c/9424487/87dd0b0da113/fcell-10-943127-g007.jpg

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