Retinoic Acid Regulation of Airway Smooth Muscle Differentiation in the Developin

视黄酸对发育中气道平滑肌分化的调节

• 批准号: 8596069
• 负责人: Hector Antonio Marquez
• 金额: $ 3.91万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596069
• 关键词: Address; Adult; Asthma; Binding; Biological Assay; Blood Vessels; Boston; Candidate Disease Gene; Cell Line; Cells; Child; Childhood Asthma; Chromatin; Chromatin Remodeling Factor; Cultured Cells; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Sequence; Development; Differentiation and Growth; Down-Regulation; Embryo; Environment; Epigenetic Process; Fostering; Gene Expression; Genes; Genetic; Genomics; Goals; In Situ Hybridization; Label; Life; Link; Lung; Mediating; Mentorship; Mesenchymal; Methylation; Modeling; Modification; Mus; Muscle Development; Pathogenesis; Pattern; Phenotype; Play; Primitive foregut structure; Promoter Regions; Regulation; Reporter; Reporting; Research; Research Personnel; Respiratory physiology; Retinoic Acid Receptor; Role; Serum; Site; Smooth Muscle; Smooth Muscle Myocytes; Suggestion; Testing; Thick; Training; Tretinoin; Universities; Up-Regulation; Visceral; Vitamin A; Vitamin A Deficiency; airway hyperresponsiveness; bisulfite; chromatin remodeling; disorder prevention; histone modification; insight; lung development; medical schools; mouse model; novel; novel strategies; postnatal; prenatal; prevent; programs; public health relevance; respiratory smooth muscle

DESCRIPTION (provided by applicant): Our broad goal is to investigate how retinoic acid (RA), the active form of vitamin A, influences the development of airway smooth muscle (SM) in the prenatal state and its effects in adult life. Maternal vitamin A deficiency has been shown to have deleterious impact in postnatal lung function in children. Vitamin A has been associated with airway hyper-reactivity and low levels have been associated with children with persistent asthma. The mechanisms that control growth and differentiation of airway SM in developing and adult lung are not well understood. RA is a well-known regulator of cellular activities in adult vascular and visceral smooth muscle and plays a vital role in lung development. Our initial studies show SM genes associated with a contractile phenotype were upregulated in RA-deficient foreguts while synthetic phenotype genes were upregulated in RA-sufficient cultures. Embryonic lung from control and a genetic RA deficient model showed similar pattern in gene expression. RA was also shown to induce expression of genes associated with epigenetic modifications. Subsequent analysis pointed to Jarid2 and Dnmt3b as epigeneitc candidates which RA likely targets to mediate the RA effects on SM phenotype. The induction of these candidate genes were also confirmed in lung specific mesenchymal cell lines. This induction of epigenetic regulators was accompanied by downregulation of genes associated with the contractile phenotype. This suggests airway SM phenotype and development are regulated by epigenetic changes which are influenced by RA. Here, we aim to determine the mechanism by which RA regulates airway SM differentiation via epigenetic controls. To this end, we will address the following aims: 1) Characterize DNA methylation status of SM gene expression influenced by RA during differentiation of lung mesenchymal cells; 2) Characterize histone modifications and binding of chromatin remodeling complexes in SM gene regulated by RA. These aims will be accomplished by using both mesenchymal cell line and embryonic lung cultures to investigate the proposed RA-related changes in airway SM gene expression and epigenetic mechanisms associated with their regulation. These studies will benefit from the expertise, mentorship, and cutting edge research environment provided and fostered by The Pulmonary Center at Boston University School of Medicine who has offered a long standing and successful platform for training young investigators. Results from this proposed research plan will provide a new insight into the regulation of the SM differentiation program that may be critical in the pathogenesis of airway hyper-reactivity. These findings may then reveal new approaches in treatment and prevention of disease such as asthma.

描述（由申请人提供）：我们的主要目标是研究维甲酸（RA），维生素A的活性形式，如何影响产前状态下气道平滑肌（SM）的发育及其在成年生活中的影响。母亲维生素A缺乏已被证明对儿童出生后肺功能有有害影响。维生素A与气道高反应性有关，维生素A水平低与儿童持续性哮喘有关。发育期和成年期气道SM生长分化的调控机制尚不清楚。RA是一种众所周知的成人血管和内脏平滑肌细胞活动调节剂，在肺发育中起重要作用。我们的初步研究表明，与收缩表型相关的SM基因在ra缺乏的前肠中上调，而合成表型基因在ra充足的培养中上调。来自对照组和遗传RA缺陷模型的胚胎肺显示相似的基因表达模式。RA还可诱导与表观遗传修饰相关的基因表达。随后的分析指出Jarid2和Dnmt3b是RA可能靶向的表观遗传学候选基因，介导RA对SM表型的影响。这些候选基因的诱导作用也在肺特异性间充质细胞系中得到证实。这种表观遗传调控因子的诱导伴随着与收缩表型相关的基因的下调。这表明气道SM的表型和发育受类风湿关节炎影响的表观遗传变化调控。在这里，我们的目的是确定RA通过表观遗传控制调节气道SM分化的机制。为此，我们将研究以下目标：1)研究RA对肺间充质细胞分化过程中SM基因表达的DNA甲基化状态；2)表征RA调控的SM基因组蛋白修饰和染色质重塑复合物的结合。这些目标将通过使用间充质细胞系和胚胎肺培养来研究ra相关的气道SM基因表达变化及其调控相关的表观遗传机制。这些研究将受益于波士顿大学医学院肺中心提供的专业知识，指导和尖端的研究环境，该中心为培训年轻研究者提供了一个长期和成功的平台。这一研究计划的结果将为SM分化程序的调控提供新的见解，这可能是气道高反应性发病机制的关键。这些发现可能会揭示治疗和预防哮喘等疾病的新方法。