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

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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.