Epigenetics participate in neonatal CLD

表观遗传学参与新生儿 CLD

• 批准号: 8670012
• 负责人: KURT H ALBERTINE
• 金额: $ 46.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670012
• 关键词: Affect; Agonist; Alveolar; Animal Model; Animals; Apoptosis; Bronchopulmonary Dysplasia; Cell Proliferation; Characteristics; Complex; DNA; DNA Methylation; DNA Modification Process; Data; Environmental air flow; Epigenetic Process; Equilibrium; Event; Exons; Frequencies; Genes; Genetic Transcription; Genomics; Histology; Histone Code; Histone Deacetylase Inhibitor; Histones; Human; Hypermethylation; Insulin-Like Growth Factor I; Intervention; Lung; Mechanical ventilation; Mechanics; Mesenchymal; Methylation; Modeling; Modification; Molecular; Nose; Pathogenesis; Physiological; Premature Birth; Regulation; Research; Research Design; Respiratory physiology; Site; Testing; Transcription Initiation; Transcription Initiation Site; Tretinoin; Ventilator Weaning; Vitamin A; gain of function; genome-wide; histone modification; improved; innovation; loss of function; novel; premature; prevent; respiratory gas; response

DESCRIPTION (provided by applicant): Preterm birth and mechanical ventilation (MV) trigger a pulmonary response. The response results in neonatal chronic lung disease (CLD), characterized by alveolar simplification. However, the mechanisms through which prematurity and MV combine to dysregulate alveolar formation are not well defined. A potential mechanism is epigenetics, which uses histone covalent modifications and DNA CpG methylation to regulate gene transcription. Premature lambs develop neonatal CLD when managed by MV but not high-frequency nasal ventilation (HFNV). Our other novel discoveries are that MV causes pulmonary 1) genome-wide hypoacetylation and hypermethylation of histone 3 (H3); 2) increased expression of insulin-like growth factor-1 (IGF-1); and 3) disruption of the histone code along the IGF-1 gene locus. Our focus on the regulation of IGF-1 expression is relevant because preterm humans with neonatal CLD have increased pulmonary IGF-1 expression. Another novel discovery is that these epigenetic changes do not happen with HFNV. Exciting new data suggest that two interventions (histone deacetylase [HDAC] inhibitors; vitamin A+retinoic acid, VARA) during MV improve alveolar formation and change epigenetic characteristics. These new data suggest that epigenetics participate in neonatal CLD. Our central hypothesis is that preterm birth and MV dysregulate histone covalent modifications and DNA CpG methylation in the lung compared to HFNV in a well-established animal model of neonatal CLD. Because the focus of our proposal is epigenetic mechanisms, we will also use HDAC inhibitors or VARA) during MV to inhibit the dysregulation caused by MV alone on pulmonary epigenetics, histology, respiratory gas exchange, and pulmonary mechanics. Specific Aim 1 will determine whether MV causes genome-wide dysregulation of H3 covalent modifications and DNA methylation in the lung. Specific Aim 2 will determine whether MV dysregulates IGF-1 histone covalent modifications and DNA methylation at functionally important regions that determine gene recognition sites and gene transcription initiation, exon selection, elongation, and termination. Specific Aim 3 will determine whether increased pulmonary IGF-1 expression during MV contributes to alveolar simplification and poor lung function. Our proposal is innovative because it tests the hypothesis that preterm birth and MV change epigenetic characteristics and alveolar formation in parallel. Our study design drills-down from pulmonary genome-wide histone modifications and DNA CpG methylation to the histone code along the IGF-1 gene locus, and relates the results to alveolar formation, respiratory gas exchange, and lung mechanics. Our track record provides confidence that we can accomplish these complex and long studies, in which we will use our unique large-animal, physiological model of neonatal CLD. We will use IGF-1 as a paradigm because of our unique expertise on IGF-1 epigenetics. The significance of our proposal is that it has the potential to shift the paradigm about both the molecular and physiologic pathogenesis of neonatal CLD.

描述（由申请人提供）：早产和机械通气（MV）会引发肺部反应。该反应导致新生儿慢性肺病（CLD），其特征是肺泡简化。然而，早产和肺泡形成失调的机制尚不清楚。一个潜在的机制是表观遗传学，它使用组蛋白共价修饰和DNA CpG甲基化来调节基因转录。当使用MV而不是高频鼻通气（HFNV）时，早产羔羊会发生新生儿CLD。我们的其他新发现是MV引起肺1)全基因组组蛋白3 （H3）的低乙酰化和高甲基化；2)胰岛素样生长因子-1 （IGF-1）表达升高；3)沿IGF-1基因位点的组蛋白编码的破坏。我们对IGF-1表达调控的关注是相关的，因为患有新生儿CLD的早产儿肺部IGF-1表达增加。另一个新发现是，这些表观遗传变化不会发生在HFNV身上。令人兴奋的新数据表明，MV期间的两种干预措施（组蛋白去乙酰化酶[HDAC]抑制剂；维生素A+维甲酸，VARA）可改善肺泡形成并改变表观遗传特征。这些新数据表明表观遗传学参与了新生儿CLD。我们的中心假设是，在一个完善的新生儿CLD动物模型中，与HFNV相比，早产和MV在肺中失调组蛋白共价修饰和DNA CpG甲基化。由于我们提案的重点是表观遗传机制，我们也将在MV期间使用HDAC抑制剂或VARA)来抑制MV单独引起的肺表观遗传学，组织学，呼吸气体交换和肺力学的失调。特异性Aim 1将确定MV是否会导致肺中H3共价修饰和DNA甲基化的全基因组失调。特异性Aim 2将确定MV是否在决定基因识别位点和基因转录起始、外显子选择、延伸和终止的重要功能区域失调IGF-1组蛋白共价修饰和DNA甲基化。特异性Aim 3将确定MV期间肺IGF-1表达增加是否导致肺泡简化和肺功能不良。我们的建议是创新的，因为它验证了早产和MV平行改变表观遗传特征和肺泡形成的假设。我们的研究设计从肺全基因组组蛋白修饰和DNA CpG甲基化深入到IGF-1基因位点上的组蛋白编码，并将结果与肺泡形成、呼吸气体交换和肺力学联系起来。我们的记录提供了信心，我们可以完成这些复杂和长期的研究，在这些研究中，我们将使用我们独特的大型动物，新生儿CLD生理模型。我们将使用IGF-1作为范例，因为我们在IGF-1表观遗传学方面具有独特的专业知识。我们的建议的意义在于，它有可能改变关于新生儿CLD的分子和生理发病机制的范式。