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.

项目摘要：围产期窒息后缺氧和缺血（HI）相关的脑损伤是死亡的主要原因和终身原因残疾，每年在美国有20,000名新生儿发生。雌性新生儿多两倍对围产期窒息的作用有抵抗力，这种现象是鲜为人知的。我们最近的研究已经在小鼠新生儿HI之后，在神经保护中表现出类似的女性偏见，并且显然具有与雌激素受体α（ERA）有关，赋予了这种性别特异性神经保护机制。我们最近报道，时代上调通过与神经营养蛋白受体，酪氨酸激酶B（TRKB）的串扰，已证明发挥重要作用 HI后新生儿小鼠的神经保护作用和改善长期功能恢复。管理 7,8-二羟基氟烷（7,8-DHF；有效和选择性的TRKB激动剂）增加TRKB磷酸化和女性的海马神经元生存，但在雄性刚出生的小鼠中没有，这些特定于雌性的小鼠 ERA NULL突变小鼠没有影响。在初步实验中，我们发现女性特异性 HI后海马时代的上调取决于脱甲基DNA修复因子，生长停滞和DNA损伤诱导蛋白45β（GADD45B）。此外，当我们用在围产期期间，睾丸激素（T）随后的HI诱导海马时代的表达为降低到男性水平。在拟议的实验中，我们将确定性别特定的机制 ERA表达和神经保护发生在新生儿HI之后，并询问信号传导途径与TRKB进行介导ERA串扰，从而赋予其神经保护作用。我们将测试以下目标在体内和体外缺血之后的小鼠和性别的海马神经元中，在AIM 1中，我们将询问膜时代信号传导是否介导HI后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AIM 2中，我们将询问是否敲除 GADD45B以女性特异性方式改变了ERA基因启动子区域的甲基化状态体外缺血。在AIM 3中，我们将评估围产期睾丸激素暴露对改变的影响 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新的假设是，性别特异性TRKB磷酸化是由HI诱导的ERA上调介导的。一个对基于性别的HI敏感性的机制的了解得以提高，将提供新的途径用于未来开发新生儿HI的药物疗法。