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

产前维生素A缺乏对成人呼吸道细胞命运改变的影响 高反应性 摘要 该项目的重点是为人类疾病定义一种新的机制。研究团队包括专家 测试发展、表观基因组学、发育生物学、哮喘遗传学、系统生物学和种群 遗传学。我们的重点是健康和疾病的发育起源(DOHAD)，它将宫内联系起来 对成体表型的干扰。一般说来，这是通过测试可遗传转录的 调节(表观遗传)机制在后代中被改变，以允许对过去暴露的记忆(细胞 重新编程模型)。我们的新模型专注于细胞谱系承诺过程中发生的扰动， 导致了成年器官中细胞的改变(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 目前研究很少，实际上会被细胞比例调整技术所消除 用于当前的表观遗传关联或转录学研究。这个项目试图确定是否 DOHaD领域可能受益于考虑细胞命运模型来理解发育对 成体表型。 我们建议使用鼠标系统来测试“细胞重编程”和“细胞命运”模型。我们会 应用组织病理学方法了解发育中和发育中的细胞亚型组成 并将增加相关的表型分析，将变化与肺功能联系起来。我们将进行基因组测试- 使用我们的双荧光小鼠进行广泛的测试，以提高我们检测细胞重新编程和细胞的能力 肺中发育的呼吸道平滑肌细胞的命运改变，并将绘制介导细胞命运的基因座 对产前维生素A(维甲酸)缺乏的反应。遗传背景差异的影响将是 测试以确定维甲酸如何与DNA序列多态性相互作用，以调节细胞和 表型差异。然后我们将使用鼠标信息来测试调节基因座在 小鼠基因组与人类全基因组中与肺功能相关的基因组是同源的 联合研究(GWAS)。通过这种方式，我们可以对基因组如何产生新的机械洞察力 与肺功能变异性相关的区域调节它们的影响，提供了一个很好的例子 如何研究基因与环境的互作。

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.