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控的表观遗传机制 脑动脉交感神经支配与α 1肾上腺素能受体亚型 项目概述：在过去的世纪中，早产率呈上升趋势 同时降低了生存能力的年龄限制。早产儿更容易 脑出血、脑室内出血及相关的脑血管病 这是由于出生过程中的压力造成的。相反，术语胎儿是 能够自动调节脑血流（CBF），尽管全身压力增加， 最大限度地减少应力引起的损伤的发生。最近，我们已经证明， 早产儿缺乏脑血流（CBF）自动调节与 交感神经（肾上腺素能）系统的不成熟。与此同时，我们也有 表明肾上腺素能系统随着发育而经历显著的成熟。 在这项研究中，我们试图确定早产儿的机制， 可以有更大的大脑自动调节能力，正如在新生羔羊中观察到的那样。在 前三个具体目标，离体，我们将研究DNA甲基化，组蛋白 修饰，microRNA和lncRNA对三种α 1肾上腺素能受体表达的影响 受体亚型在早产儿，近足月胎儿，新生羔羊，成年羊。在 第四个具体目标，在体内，在长期插管的早产儿，近足月胎儿， 新生羔羊和成年绵羊，我们将确定DNA甲基化，组蛋白 CBF调节中的修饰、microRNA、lncRNA和α 1-肾上腺素能受体亚型 两性都有发育。总的来说，这些研究将提供重要的见解， 交感神经调节CBF与发展，并建议的方法，以防止或 改善CBF失调。