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.

胎儿、新生儿和成人发育调节的表观遗传学机制 大脑动脉交感神经支配与α1肾上腺素能受体亚型 项目摘要：在过去的半个世纪里，早产率一直在上升 同时降低了生存能力的年龄限制。早产儿更容易患上 生发基质和其他脑内出血、脑室出血及相关 在分娩过程中由于压力而产生的问题。相反，术语-胎儿是 能够自动调节脑血流量(flow，CBF)，尽管全身压力和 最大限度地减少应激导致出血的发生。最近，我们已经证明了 早产儿缺乏脑血流量(flow，CBF)自我调节与 交感神经(肾上腺素能)系统不成熟。与此相一致的是，我们还有 表明肾上腺素能系统在发育过程中经历了明显的fi不成熟。 在拟议的研究中，我们试图确定早产儿 可以有更强的大脑自动调节能力，就像在新生的羔羊身上观察到的那样。在 在体外，我们将研究fi甲基化、组蛋白在fi中的作用 Modifi阳离子、microRNA和lncRNA对三种α1肾上腺素能受体表达的影响 早产儿、近月儿、新生羔羊和成年绵羊的受体亚型。在 在体内，慢性导尿管早产儿、近月儿、早产儿、 新生羔羊和成年绵羊，我们将测定DNA甲基化、组蛋白的影响 fi阳离子、MicroRNA、LncRNA和α1-肾上腺素能受体亚型在脑血流调节中的作用 在两性中都有发展。总体而言，这些研究将为 同情CBF的调节与发展，并提出预防或 改善脑血流量失调。