Epigenetic Mechanisms of Developmental Regulation of Fetal, Newborn, and Adult Cerebral Artery Sympathetic Innervation and Alpha1 Adrenergic Receptor Subtypes

胎儿、新生儿和成人脑动脉交感神经支配和α1肾上腺素能受体亚型发育调节的表观遗传机制

• 批准号: 9237948
• 负责人: Ravi Goyal
• 金额: $ 39.5万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237948
• 关键词: AR gene; Adrenergic Agents; Adrenergic Receptor; Adult; Age; Animals; Azacitidine; Behavior Disorders; Birth; Blood Vessels; Blood flow; Brain; Catheters; Cerebral Palsy; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Chronic; Clinical; DNA; DNA Methylation; Data; Development; Developmental Delay Disorders; Epigenetic Process; Female; Fetus; Gene Expression; Genes; Hemorrhage; Homeostasis; Human; Hydrostatic Pressure; In Vitro; Individual; Intubation; Life; Measures; Mediating; Mental Retardation; Messenger RNA; MicroRNAs; Modification; Molecular; Morphology; Neonatal; Nerve; Neurologic; Neurologic Deficit; Newborn Infant; Pathology; Perinatal subependymal hemorrhage; Periventricular Leukomalacia; Play; Premature Birth; Prematurity of fetus; Prevalence; Prevention; Process; Regulation; Resistance; Role; Rupture; Sheep; Signal Transduction; Stress; System; Testing; Transferase; Translational Regulation; Translations; Untranslated RNA; Validation; age group; alpha-1 adrenergic receptors; cerebral artery; cerebrovascular; epigenetic regulation; fetal; histone acetyltransferase; histone methyltransferase; histone modification; in vivo; inhibitor/antagonist; insight; intraventricular hemorrhage; male; neonatal hypoxic-ischemic brain injury; nerve supply; premature; pressure; preterm newborn; prevent; promoter; response; sex; stressor

Title: Epigenetic Mechanisms of Developmental Regulation of Fetal, Newborn, and Adult Cerebral Artery Sympathetic Innervation and Alpha1 Adrenergic Receptor Subtypes Project Summary: During the past half century there has been the rising rate of preterm birth combined with a lowering of the age limit of viability. The premature fetus is more prone to germinal matrix and other intracerebral hemorrhage, intraventricular hemorrhage, and related problems as a consequence of stress during the process of birth. In contrast, the term-fetus is able to autoregulate cerebral blood flow (CBF) despite the increase in systemic pressure and minimize the occurrence of stress-induced hemorrhages. Recently, we have demonstrated that lack of cerebral blood flow (CBF) autoregulation in the premature fetus is associated with immaturity of the sympathetic (adrenergic) system. In concert with this, we also have demonstrated that the adrenergic system undergoes a significant maturation with development. In the proposed studies, we attempt to determine the mechanisms by which the premature fetus can have greater cerebral autoregulation capability, as observed in the newborn lamb. In the first three specific aims, ex-vivo, we will examine the role of DNA methylation, histone modifications, microRNA, and lncRNA on the expression of the three alpha 1 adrenergic receptor subtypes in premature fetus, near-term fetus, newborn lamb, and adult sheep. In the fourth specific aim, in vivo, in the chronically catheterized preterm fetus, near-term fetus, newborn lamb, and adult sheep, we will determine the effect of DNA methylation, histone modifications, microRNAs, lncRNA, and alpha 1-adrenergic receptor subtypes in CBF regulation with development in both the sexes. Overall, these studies will provide vital insights in the sympathetic regulation of CBF with development, and suggest approaches to prevent or ameliorate CBF dysregulation.

标题：胎儿、新生儿和成人发育调节的表观遗传机制 脑动脉交感神经支配和 Alpha1 肾上腺素能受体亚型 项目概要：在过去的半个世纪里，早产率不断上升 加上生存年龄限制的降低，早产儿更容易发生。 生发基质和其他脑出血、脑室内出血及相关 相比之下，胎儿一词是由于出生过程中的压力而产生的问题。 尽管全身压力增加，但仍能够自动调节脑血流量（CBF） 最近，我们已经证明，最大程度地减少应激性出血的发生。 早产儿缺乏脑血流（CBF）自动调节与 交感神经（肾上腺素）系统的不成熟与此相一致。 肾上腺素能系统随着发育而经历显着的成熟。 在拟议的研究中，我们试图确定早产儿的机制 正如在新生羔羊身上观察到的那样，它具有更强的大脑自动调节能力。 前三个具体目标，体外，我们将检查 DNA 甲基化、组蛋白的作用 修饰、microRNA 和 lncRNA 对三种 α1 肾上腺素能表达的影响 早产胎儿、近足月胎儿、新生羔羊和成年绵羊的受体亚型。 第四个具体目标，在体内，在长期插入导管的早产胎儿、近足月胎儿中， 新生羔羊和成年绵羊，我们将确定 DNA 甲基化、组蛋白的影响 CBF 调节中的修饰、microRNA、lncRNA 和 α1-肾上腺素能受体亚型 总的来说，这些研究将为两性的发展提供重要的见解。 CBF 与发育的交感调节，并提出预防或预防方法 改善 CBF 失调。