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 脑动脉交感神经和α1肾上腺素能受体亚型 项目摘要：在过去的半个世纪中，早产率上升 结合降低生存能力的年龄极限。过早的胎儿更容易 生发基质和其他脑内出血，脑室内出血和相关 出生过程中压力的原因。相比之下，术语是 它可以自动调节大脑血流（CBF）努力全身压力和 最小化应激诱导的出血的发生。最近，我们证明了 过早胎儿缺乏脑血流（CBF）自动调节与 交感神经（肾上腺素）系统的不成熟。与此一起，我们也有 证明肾上腺素系统经历了与发展的重要成熟。 在拟议的研究中，我们试图确定过早胎儿的机制 如新生儿羔羊所观察到的那样，可以具有更大的大脑自动调节能力。在 前三个特定的目的，即事实，我们将检查DNA甲基化，组蛋白的作用 在三个α1肾上腺的表达上的修改，microRNA和lncRNA 早产胎儿，近期胎儿，新生羔羊和成年绵羊的受体亚型。在 在长期导管的早产胎胎胎胎胎胎胎胎胎胎胎胎的第四个特定目标，近期胎儿 新生儿羔羊和成年绵羊，我们将确定DNA甲基化的作用，组蛋白 CBF调节中的修改，microRNA，LNCRNA和α1-肾上腺素受体亚型 随着男女的发展。总体而言，这些研究将为您提供重要的见解 通过开发对CBF的同情调节，并提出了预防或 改善CBF失调。