IMPACT OF PRENATAL VITAMIN A DEFICIENCY ON CELL FATE ALTERATIONS IN ADULT AIRWAY HYPERRESPONSIVENESS

胎儿期维生素A缺乏对气道细胞命运的影响 高反应 摘要 该项目的重点是确定人类疾病的新机制。研究小组包括专家 在检测开发、表观基因组学、发育生物学、哮喘遗传学、系统生物学和人口 遗传学我们的重点是健康和疾病的发育起源（DOHaD），它将子宫内 对成人表型的干扰。一般来说，这是通过测试是否遗传转录 调节（表观遗传）机制在后代中发生改变，以允许对过去暴露的记忆（细胞 重编程模型）。我们的新模型专注于细胞谱系定型过程中发生的扰动， 导致成体器官中细胞库的改变（细胞命运模型）。 虽然细胞命运模型得到了初步数据的支持，并具有介导成人疾病的主要潜力，但它 是目前非常不足的研究，事实上，将消除细胞比例调整技术 用于目前的表观遗传关联或转录组学研究。本项目旨在确定 DOHaD领域可以从考虑细胞命运模型中受益，以了解发育对 成人表型 我们建议使用小鼠系统测试“细胞重编程”和“细胞命运”模型。我们将 应用组织病理学方法来了解细胞亚型组成的发展和发达国家 并将增加相关的表型测定，以将变化与肺功能联系起来。我们将进行基因组- 使用我们的双荧光小鼠进行广泛的测定，以改善我们检测细胞重编程和细胞凋亡的能力。 肺中发育中的气道平滑肌细胞的命运变化，并将绘制介导细胞命运的基因座 产前维生素A（视黄酸）缺乏的反应。遗传背景差异的影响将是 测试以确定视黄酸如何与DNA序列多态性相互作用以介导细胞和 表型差异然后，我们将使用小鼠信息来测试小鼠中的调节位点的可能性 小鼠基因组与人类全基因组中与肺功能相关的基因组直系同源 关联研究（GWAS）。通过这种方式，我们可以产生新的机制见解，了解基因组如何 与肺功能变异性相关的区域介导了它们的影响，提供了一个很好的例子， 如何研究基因与环境的相互作用

IMPACT OF PRENATAL VITAMIN A DEFICIENCY ON CELL FATE ALTERATIONS IN ADULT AIRWAY HYPERRESPONSIVENESS ABSTRACT This project is focused on defining a novel mechanism for human disease. The research team includes experts in assay development, epigenomics, developmental biology, asthma genetics, systems biology, and population genetics. Our focus is on the Developmental Origins of Health and Disease (DOHaD), which links intrauterine perturbations to adult phenotypes. In general, this is pursued by testing whether heritable transcriptional regulatory (epigenetic) mechanisms are altered in offspring to allow a memory of past exposure (the cellular reprogramming model). Our new model is focused on perturbations occurring during cell lineage commitment, leading to an altered repertoire of cells in an adult organ (the cell fate model). While the cell fate model is supported by preliminary data and has major potential to mediate adult disease, it is currently very understudied, and would in fact be eliminated by the cell proportion adjustment techniques used in current epigenetic association or transcriptomic studies. This project seeks to establish whether the DOHaD field could benefit from considering the cell fate model in understanding developmental influences on adult phenotypes. We propose to test both the “cellular reprogramming” and the “cell fate” models using a mouse system. We will apply histopathological approaches to understand cell subtype composition of developing and developed organs and will add correlative phenotypic assays to link changes with lung function. We will perform genome- wide assays using our double fluorescent mice to refine our ability to detect cellular reprogramming and cell fate changes in developing airway smooth muscle cell in the lung, and will map the loci mediating the cell fate responses to prenatal vitamin A (retinoic acid) deficiency. The effect of genetic background differences will be tested to define how retinoic acid interacts with DNA sequence polymorphism to mediate cellular and phenotypic differences. We then will use the mouse information to test the possibility that the regulatory loci in the mouse genome are orthologous to those associating pulmonary functions in human genome-wide association studies (GWAS). In this way, we can generate novel mechanistic insights into how genomic regions associated with pulmonary function variability mediate their effects, providing an excellent example of how to study gene x environment interactions.