Estradiol and Hippocampal Development

雌二醇和海马发育

基本信息

批准号：
9052240
负责人：
MARGARET M. MCCARTHY
金额：
$ 38.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052240
关键词：
Acetylation Adult Androgens BDNF gene Biological Birth Brain Brain-Derived Neurotrophic Factor Candidate Disease Gene Cells Chromatin Chromosomes Complement DNA DNA Methylation Development Dose Epigenetic Process Estradiol Estrogens Female Gene Expression Genes Goals Health Hippocampal Formation Hippocampus (Brain)Histone Deacetylase Inhibitor Histones Hormonal Hormones Injury Laboratory Rat Mediating Messenger RNA Methylation MicroRNAs Modification Natural regeneration Nature Neonatal Neonatal Brain Injury Neuronal Differentiation Neurons Neurosciences Newborn Infant Outcome Perinatal Process Production Regulation Regulator Genes Repression Role Sex Characteristics Sex Differentiation Source Steroids Surveys Time base dentate gyrus epigenetic regulation histone modification insight interest male methylome neonate neurogenesis neuroprotection novel postnatal promoter tool

项目摘要

DESCRIPTION (provided by applicant): Understanding neurogenesis is an essential goal of neuroscience. Naturally occurring sex differences in neurogenesis are of inherent interest but also provide a tractable tool for exploring novel mechanisms not otherwise apparent. Using the laboratory rat we have identified and characterized a profound sex difference in hippocampal neurogenesis restricted to a perinatal sensitive period. Newborn males make up to twice as many new cells as females in the dentate gyrus, CA1 and to a lesser extent CA3 of the hippocampal formation, and 80% of those newborn cells will become neurons while only 40% will do so in females. Thus males have higher rates of both proliferation and neuronal differentiation. Sex differences in the brain are often the byproduct of increased testicular androgen production that is locally converted to estradiol in the brain. We propose the novel hypothesis that the sex difference in hippocampal neurogenesis is the product of two sources of epigenetic repression in females; 1) canonical changes to the DNA and histones via methylation and acetylation that repress pro-proliferation genes, and 2) microRNAs which regulate gene expression by degrading pro-differentiation mRNAs. We further contend that the higher level of microRNAs we detect in neonatal female hippocampus is at least in part determined by chromosome compliment, that is, XX vs XY. A candidate gene, BDNF, has emerged and detailed interrogation of BDNF gene expression and effects will be combined with broader based surveys of the hippocampal methylome and chromatin state to elucidate the source of the sex difference in neurogenesis via the following specific aims: SA1 - Identify the mechanism mediating sex differences in epigenetic control of neurogenesis in the developing hippocampus, SA2 - Determine microRNA profile and mechanism suppressing neurogenesis in developing female hippocampus and SA3 - Establish cross-talk between epigenetics and microRNAs in neonatal hippocampal neurogenesis. Completion of these aims will provide novel insight into the regulation of neurogenesis in the developing healthy brain and illuminate the source of higher male vulnerability to the consequences of neonatal brain injury or insult.

描述（由申请人提供）：了解神经发生是神经科学的一个基本目标。神经发生中自然发生的性别差异具有内在的意义，但也为探索不明显的新机制提供了一种易于处理的工具。使用实验室大鼠，我们已经确定并表征了仅限于围产期敏感期的海马神经发生的深刻性别差异。新生男性的齿状回、CA1 和海马结构的 CA3 中的新细胞数量是女性的两倍，其中 80% 的新生细胞将成为神经元，而女性中只有 40% 会成为神经元。因此，男性具有更高的增殖率和神经元分化率。大脑中的性别差异通常是睾丸雄激素产生增加的副产品，雄激素在大脑中局部转化为雌二醇。我们提出了一个新的假设，即海马神经发生的性别差异是女性表观遗传抑制的两个来源的产物； 1) 通过甲基化和乙酰化对 DNA 和组蛋白进行典型改变，抑制促增殖基因；2) microRNA 通过降解促分化 mRNA 来调节基因表达。我们进一步认为，我们在新生儿女性海马体中检测到的较高水平的 microRNA 至少部分是由染色体互补决定的，即 XX 与 XY。候选基因 BDNF 已经出现，对 BDNF 基因表达和影响的详细研究将与对海马甲基化组和染色质状态的更广泛的调查相结合，以通过以下具体目标阐明神经发生中性别差异的根源：SA1 - 识别介导发育中海马神经发生表观遗传控制性别差异的机制，SA2 - 确定 microRNA 谱和抑制发育中女性海马神经发生的机制和 SA3 - 建立串扰新生儿海马神经发生中的表观遗传学和 microRNA 之间的关系。这些目标的完成将为发育中的健康大脑的神经发生调节提供新的见解，并阐明男性更容易受到新生儿脑损伤或侮辱后果影响的根源。