Type I IFN signaling during lung development in Down Syndrome

项目摘要/摘要 唐氏综合征(DS)，又称21三体，是人类最常见的染色体异常， 每700名活产儿中就有1名受到影响。虽然DS可以影响到许多器官系统，但肺病和心脏病是最主要的 导致发病和死亡的原因。在患有DS的个体中，报告了几种先天性肺异常，包括 呼吸道分支缺陷，分支数量减少25%，上呼吸道肌肉减少 吞咽困难和/或支气管软化症。这些并发症在成年后一直存在，与之相反 变得更严重，因此很可能是由于发育不足。 虽然已经描述了儿童和成人DS患者的肺结构和功能异常，但 定义这些异常的个体发育的数据有限。我们推测，一些发育差异 可以在产前启动。为这项应用开发的初步数据显示，DS胎儿肺，从 早在妊娠16周时，出现明显的终末气管/腺泡小管扩张。 淋巴管和肌肉动脉。此外，我们发现肺组织中I型干扰素信号转导靶点的表达增加 DS与非DS胎肺中MX1、IFI27等基因的比较。干扰素信号在细胞中起着关键作用 分化、增殖、凋亡和细胞外基质的产生是肺发育的重要事件。最后，我们的 初步数据显示，DS肺表现出与ECM相关的蛋白、调节因子和 分泌因子(FN1、COL6等)。因此，我们假设DS的肺缺陷可以在胎儿时期开始。 细胞增殖、分化和细胞外基质产生中依赖干扰素的变化起作用。 这些缺陷。为了检验这个假说，我们将1)检验形态、细胞和分子的假说 DS患者在胎儿发育的假腺/管早期阶段就开始出现异常 使用组织病理学分析和单细胞测序，2)检验I型过量的假设 干扰素信号干扰DS胎肺发育过程中的细胞分化和呼吸道分支，以及3)试验 过多的干扰素信号干扰DS胎肺发育期间ECM的产生的假说。为 目标2和3，我们将使用我们发表的胎儿肺外植体培养模型和上皮器官培养。 单独或与间充质细胞共同培养检测I型干扰素信号的得失作用 对细胞分化和细胞外基质产生的影响。 这些研究有望提高我们对关键的分子和细胞差异的理解，以及 DS发育期肺分支缺陷的控制机制。这项工作的创新之处在于 可能会产生巨大的整体影响，并促进DS患者治疗的翻译潜力 与其他表现为肺发育不良的先天性肺畸形一样。

Project Summary/Abstract Down syndrome (DS), also referred to as trisomy 21, is the most common human chromosomal anomaly, affecting 1 in 700 live births. Although DS can affect many organ systems, lung and heart disease are the leading causes of morbidity and mortality. Several congenital lung anomalies are reported in individuals with DS including airway branching defects, with a 25% decrease in the number of branches and reduced upper airway muscle tone with dysphagia and/or bronchomalacia. These complications remain constant into adulthood, as opposed to becoming exacerbated, and are hence likely due to developmental insufficiency. While abnormal pulmonary structure and function in pediatric and adult DS subjects has been described, there is limited data defining the ontogeny of these abnormalities. We postulated that some developmental differences could initiate prenatally. Preliminary data developed for this application shows that DS fetal lungs, starting as early as 16 weeks gestation, present with pronounced dilatation of terminal airways/acinar tubules, dilated lymphatics and muscularized arteries. In addition, we find increased lung expression of type I IFN signaling target genes such as MX1 and IFI27 in DS compared to non-DS fetal lungs. IFN signaling plays a critical role in cell differentiation, proliferation, apoptosis, and ECM production, important events for lung development. Finally, our preliminary data show that DS lungs exhibit altered expression of ECM affiliated proteins, regulators, and secreted factors (FN1, COL6, etc.). Therefore, we hypothesize that lung defects in DS can initiate during fetal development, and that IFN-dependent changes in cell proliferation, differentiation and ECM production contribute to these defects. To test this hypothesis, we will 1) Test the hypothesis that morphological, cellular and molecular abnormalities are initiated during the late pseudoglandular/early canalicular stages of fetal development in DS lungs using histopathological analyses and single cell sequencing, 2) Test the hypothesis that excessive type I IFN signaling disrupts cell differentiation and airway branching during fetal lung development in DS, and 3) Test the hypothesis that excessive IFN signaling disrupts ECM production during fetal lung development in DS. For aims 2 and 3, we will use our published fetal lung explants culture model as well as epithelial organoid cultures alone or co-cultured with mesenchymal cells to test the effect of gain and loss of function of type I IFN signaling on cell differentiation and ECM production. These studies have the promise to improve our understanding of the key molecular and cellular differences, and the mechanisms controlling branching defects in DS developing lungs. The innovative aspects of this work are likely to have great overall impact and facilitate the translational potential for therapies for DS individuals, as well as other lung congenital defects demonstrating hypoplastic lungs.