Sex differences in neurotrophin mediated neonatal neuroprotection: Role of ER alpha

神经营养素介导的新生儿神经保护的性别差异：ER α 的作用

基本信息

批准号：
10378722
负责人：
Pelin Cengiz
金额：
$ 34.02万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378722
关键词：
Aftercare Agonist Asphyxia Neonatorum Brain Brain Hypoxia-Ischemia Brain Injuries Cause of Death Cerebral Ischemia DNA Damage DNA Repair Disease Environment Epigenetic Process Estradiol Estrogen Receptor Status Estrogen Receptor alpha Female Foundations Future GADD45B Genes Genetic Transcription Goals Growth Hippocampus (Brain)Hormonal Hormones Hypoxic-Ischemic Brain Injury In Vitro Injury Investigational Therapies Ischemia Ischemic Brain Injury Knockout Mice Life Ligands Link Mediating Membrane Methylation Modeling Molecular Mus Mutant Strains Mice Neonatal Nerve Growth Factor Receptors Nerve Growth Factors Nervous System Physiology Neurons Newborn Infant Outcome Perinatal Pharmacotherapy Phosphorylation Physiological Play Predisposition Promoter Regions Protein Tyrosine Kinase Proteins Recovery Recovery of Function Reporting Resistance Role Severities Sex Differences Signal Pathway Signal Transduction Testing Testosterone Time United States Up-Regulation Work base biological sex demethylation design disability drug development experimental study improved in vivo insight knock-down male neonatal brain neonatal hypoxic-ischemic brain injury neonatal mice neuron apoptosis neuronal survival neuroprotection neurotrophic factor non-genomic novel perinatal period programs promoter public health priorities receptor response response to brain injury sex src-Family Kinases

项目摘要

Project Summary: Hypoxia and ischemia (HI) related brain injury after perinatal asphyxia is a major cause of death and life-long disability, occurring in 20,000 newborns every year in the United States. Female newborns are two times more resistant to the effects of perinatal asphyxia, a phenomenon that is poorly understood. Our recent studies have demonstrated a similar female bias in neuroprotection following neonatal HI in mice, and have clearly implicated estrogen receptor alpha (ERa) in conferring this sex-specific neuroprotective mechanism. We recently reported that ERa upregulation confers neuroprotection in the female neonatal hippocampus through cross-talk with the neurotrophin receptor, tyrosine kinase B (TrkB), which has been shown to play an important role in neuroprotection and improving long-term functional recovery in neonatal mice post-HI. Administration of 7,8-dihydroxyflavone (7,8-DHF; potent and selective TrkB agonist) increases TrkB phosphorylation and hippocampal neuronal survival post-HI in female, but not in male newborn mice, and these female specific effects are absent in the ERa null mutant mice. In preliminary experiments we have found that female-specific upregulation of hippocampal ERa post-HI is dependent on a demethylating DNA repair factor, the growth arrest and DNA damage-inducible protein 45 beta (Gadd45b). Additionally, when we treated females with testosterone (T) during the perinatal period, subsequent HI-induced expression of hippocampal ERa is reduced to male levels. In the proposed experiments, we will determine the mechanisms by which sex-specific ERa expression and neuroprotection occurs following neonatal HI, and interrogate signaling pathways that mediate ERa cross-talk with TrkB and thereby confer its neuroprotective effects. We will test the following aims in mice and sexed hippocampal neurons following in vivo and in vitro ischemia, respectively: In Aim 1, we will interrogate whether membrane ERa signaling mediates neuroprotection post-HI, and assess signaling mechanisms that link ERa signaling to the membrane TrkB receptor. In Aim 2, we will interrogate if knockdown Gadd45b alters the methylation status of the ERa gene promoter region in a female specific manner following in vitro ischemia. In Aim 3, we will evaluate the effects of altered perinatal testosterone exposure on ERa expression and the severity of long-term functional deficits. The work proposed in these aims will test the novel hypothesis that sex-specific TrkB phosphorylation is mediated by HI induced ERa upregulation. An improved understanding of the mechanisms underlying sex-based susceptibility to HI will provide new avenues for future development of drug therapies for neonatal HI.

项目概要：围产期窒息后缺氧和缺血（HI）相关的脑损伤是死亡和终生的主要原因美国每年有 20,000 名新生儿出现残疾。女性新生儿是其两倍对围产期窒息的影响有抵抗力，但人们对这种现象知之甚少。我们最近的研究有在小鼠新生儿 HI 后的神经保护中表现出类似的女性偏见，并且明显表明雌激素受体α（ERa）参与了这种性别特异性神经保护机制。我们最近报道 ERa 上调通过以下方式赋予女性新生儿海马神经保护作用：与神经营养蛋白受体酪氨酸激酶 B (TrkB) 的串扰，已被证明发挥重要作用在神经保护和改善新生小鼠 HI 后长期功能恢复中的作用。管理 7,8-二羟基黄酮（7,8-DHF；有效且选择性的 TrkB 激动剂）可增加 TrkB 磷酸化并雌性小鼠海马神经元在 HI 后存活，但雄性新生小鼠则不然，并且这些雌性小鼠具有特定的海马神经元存活率 ERa 无效突变小鼠中不存在这种效应。在初步实验中我们发现女性特有的 HI 后海马 ERa 的上调依赖于去甲基化 DNA 修复因子，即生长逮捕和 DNA 损伤诱导蛋白 45 β (Gadd45b)。此外，当我们对女性进行治疗时围产期睾酮 (T)，随后 HI 诱导的海马 ERa 表达为降低到男性水平。在拟议的实验中，我们将确定性别特异性的机制 ERa 表达和神经保护发生在新生儿 HI 后，并询问信号通路介导 ERa 与 TrkB 的串扰，从而赋予其神经保护作用。我们将测试以下目标分别在体内和体外缺血后的小鼠和性海马神经元中：在目标 1 中，我们将询问膜 ERa 信号传导是否介导 HI 后的神经保护，并评估信号传导将 ERa 信号传导与膜 TrkB 受体联系起来的机制。在目标 2 中，我们将询问是否击倒 Gadd45b 以女性特有的方式改变 ERa 基因启动子区域的甲基化状态体外缺血。在目标 3 中，我们将评估围产期睾酮暴露改变对 ERa 表达和长期功能缺陷的严重程度。这些目标中提出的工作将测试性别特异性 TrkB 磷酸化是由 HI 诱导的 ERa 上调介导的新假设。一个更好地了解基于性别的 HI 易感性机制将提供新的途径促进新生儿 HI 药物治疗的未来发展。