Alpha Adrenergic Methylation and Developmental Maturation of Cerebral Autoregulation in Ovine Preterm Fetus

羊早产儿的α肾上腺素能甲基化和大脑自动调节的发育成熟

• 批准号: 10661985
• 负责人: Ravi Goyal
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661985
• 关键词: Adrenergic Agents; Adrenergic Receptor; Affect; Animals; Basic Science; Biological Assay; Birth; Blood flow; Brain; Brain Injuries; Caring; Carotid Arteries; Catheterization; Cerebrovascular Circulation; Cerebrum; Child; Chronic; Circulation; DNA Methylation; Data; Development; Disabled Persons; Epigenetic Process; Epinephrine; Excision; Expenditure; Face; Family; Fetal Sheep; Fetus; Gestational Age; Healthcare; Homeostasis; Hormones; Hour; Human; Impairment; Incidence; Infant; Laser-Doppler Flowmetry; Learning Disabilities; Life; Measurement; Measures; Mediating; Methylation; Neurologic; Norepinephrine; Outcome; Pathology; Pathway interactions; Perinatal subependymal hemorrhage; Periventricular Leukomalacia; Play; Premature Infant; Regulation; Research; Resources; Role; Rupture; Series; Sheep; Side; Stress; Structure of superior cervical ganglion; Sympathetic Nervous System; System; Systemic blood pressure; Term Birth; Testing; Therapeutic; Time; alpha-1 adrenergic receptors; cerebral capillary; cognitive disability; constriction; demethylation; differential expression; disability; experimental study; fetal; gene network; in utero; in vivo; insight; life-long learning; mRNA Expression; mature animal; neonate; pressure; preterm newborn; prevent; promoter; receptor; response; sex; transcription factor

Summary: Preterm infants have a significantly higher incidence of brain damage as a consequence of immature cerebral blood flow (CBF) autoregulation. In contrast to term neonates, preterm neonates are not able to reduce CBF in response to increased systemic BP. In preterm neonates, exposure of fragile cerebral vessels to an increased amount of blood flow at elevated systemic pressure leads to their rupture and brain damage. Our preliminary studies demonstrate that near-term fetuses and term-newborn lambs can constrict carotid arteries and reduce CBF when systemic BP rises; however, this capability is not developed in the preterm fetus. Also, we observed that following the removal of sympathetic control in the near-term fetus by severing the superior cervical ganglion made them lose their ability to restrict carotid blood flow to the brain with the rise in systemic BP. We also observed that the constriction of carotid arteries to reduce CBF is regulated by the sympathetic nervous system, specifically by the activity of alpha-1 adrenergic receptors (α1-ARs). These receptors are expressed at a significantly lower number in preterm carotid arteries. Thus, we concluded that reduced activity of α1-ARs plays a fundamental role in regulating carotid blood flow with the rise in systemic BP. Furthermore, we present evidence that differential DNA methylation regulates α1-ARs promoter activity and expression. Thus, we will test the hypothesis that DNA methylation and demethylation regulate the expression and function of α1-AR subtypes (α1A-, α1B-, α1D) in the carotid arteries and play a crucial role in the maturation of CAR from preterm to term fetus. We will collect data from both sexes to identify any sex-related changes. The studies will be conducted in-vivo in chronically catheterized fetal sheep and ex-vivo on isolated carotid arteries. The hypothesis will be tested with two specific aims. Aim 1: From preterm to term fetus in a sex-specific manner, we will conduct an in-depth mechanistic analysis of promoter DNA methylation on differential expression of α1-AR subtypes in carotid arteries. Aim 2: In a sex-specific manner, we will determine the functional significance of differential α1-AR subtypes promoter methylation and expression on carotid artery contractility and blood flow. The measurements will be conducted in real-time, in-vivo, with in-utero fetal maturation. This will provide valuable information regarding the role of α1-AR subtypes and the epigenetic mechanisms involved in the maturation of CAR.

摘要：由于大脑发育不成熟，早产儿脑损伤的发生率明显更高。 血流量（CBF）自动调节 与足月新生儿相比，早产儿不能减少 CBF。 早产儿的全身血压升高，脆弱的脑血管暴露在增加的血流量中。 我们的初步研究表明，短期内系统压力升高会导致其破裂和脑损伤。 然而，当全身血压升高时，胎儿和足月新生羔羊可以收缩颈动脉并减少CBF； 此外，我们观察到，在早产儿的交感神经控制被去除后，这种能力也没有发展。 近产胎儿的颈上神经节被切断，使他们失去了限制颈动脉血流到颈动脉的能力。 我们还观察到，颈动脉收缩以减少 CBF 是受调节的。 交感神经系统，特别是通过 α-1 肾上腺素能受体 (α1-AR) 的活性。 早产儿颈动脉中的表达量显着降低，因此，我们得出结论，α1-AR 的活性降低。 随着全身血压的升高，它在调节颈动脉血流中发挥着重要作用。此外，我们还提供了证据。 差异 DNA 甲基化调节 α1-AR 启动子活性和表达 因此，我们将检验以下假设。 DNA 甲基化和去甲基化调节颈动脉中 α1-AR 亚型（α1A-、α1B-、α1D）的表达和功能 动脉，在 CAR 从早产儿到足月胎儿的成熟过程中发挥着至关重要的作用。我们将收集两性的数据。 以确定任何与性别相关的变化，这些研究将在长期插入导管的胎羊体内和体外进行。 该假设将通过两个具体目标进行检验：从早产儿到足月胎儿。 性别特异性的方式，我们将对启动子DNA甲基化的差异进行深入的机制分析 目标 2：以性别特异性的方式，我们将确定颈动脉中 α1-AR 亚型的表达。 不同α1-AR亚型启动子甲基化和表达对颈动脉收缩力和血液的意义 测量将在体内实时进行，这将为胎儿的成熟提供有价值的信息。 有关 α1-AR 亚型的作用以及参与 CAR 成熟的表观遗传机制的信息。