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Neuroimaging epigenetics of prospective postpartum depression biomarkers

前瞻性产后抑郁症生物标志物的神经影像表观遗传学

基本信息

批准号：
9276132
负责人：
Zachary Aaron Kaminsky
金额：
$ 51.32万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276132
关键词：
Affect Amygdaloid structure Biological Markers Birth Blood Blood Tests Brain Brain imaging Brain region Classification Clinic Clinical DNA Methylation DNA analysis Data Depression screen Diagnosis Discipline of obstetrics Disease Emotional Epigenetic Process Estrogens Etiology Evaluation Female Functional Imaging Functional Magnetic Resonance Imaging General Population Genes Gonadal Hormones Gynecology Health High Risk Woman Hippocampus (Brain)Hormones Image Individual Infanticide Longitudinal Studies Longitudinal cohort Measures Mediating Mental Depression Mental Health Modeling Mood Disorders Mothers Outcome Oxytocin Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Population Postpartum Depression Postpartum Period Pregnancy Progesterone Prospective cohort Recording of previous events Recruitment Activity Research Design Research Personnel Rest Risk Sampling Series Serum Short-Term Memory Synaptic plasticity Talents Testing Third Pregnancy Trimester Time Translating Woman antenatal base cognitive performance cohort comparison group depressive symptoms endophenotype epigenetic marker epigenetic variation epigenomics experience experimental study follow-up genome-wide analysis high risk population hippocampal subregions imaging study improved methylation biomarker molecular pathology neurogenesis neuroimaging novel offspring postnatal predictive marker prospective psychologic public health relevance response sample collection screening single episode major depressive disorder therapeutic target trait

项目摘要

DESCRIPTION (provided by applicant): This is a application to implement blood based screening for postpartum depression (PPD) using a novel epigenetic biomarker we have developed, enabling the longitudinal evaluation of PPD specific neuroimaging phenotypes in the postpartum period in individuals at risk and in matched controls. The project will take advantage of the talents of a leader in the field of women's mental health and PPD, a highly experienced DNA methylation and biomarker researcher, and an accomplished neuroimager. Through a recent cross species translational experiment investigating hippocampal epigenetic responses to estrogen and epigenomic profiling in a prospective sample of women at risk for PPD, we identified a set of epigenetic marks functionally related to modulating synaptic plasticity and capable of predicting PPD with >85% accuracy. Our results indicated that risk to PPD is mediated by an increased sensitivity to estrogen. The availability of peripheral biomarkers opens novel opportunities to perform imaging epigenetics in the PPD population. While there is some consistency across MDD and PPD specific neuroimaging phenotypes, it is unclear if these findings represent disease etiology or the state of depression and requires longitudinal study in spontaneous and previous mood disorder diagnosed cases to elucidate. The central hypothesis is that PPD risk may arise due to an altered sensitivity of the epigenetic reprogramming machinery in response to gonadal hormones and that peripherally measured epigenetic variation at these loci will be associated with longitudinally progressive depression associated neuroimaging phenotypes including resting state functional connectivity alterations of corticolimbic pathways, emotional processing, working memory, and hippocampal subregion specific activity changes in the postpartum period. In Aim 1, we will use standard third trimester blood draws to perform PPD prediction and generate a sample of women at risk for PPD from the general population and from women with a previous history of mood disorder. In Aim 2, we will perform a series of fMRI tests to assess resting state functional connectivity, emotional response, working memory, and hippocampal subregion specific alterations at both a pre-depression time point of two weeks at six weeks during major depressive episodes. A within groups comparison will identify trait associated endophenotypes that will be integrated with epigenetic, serum hormone, and psychological data in Aim 3. The analyses performed will identify novel brain endophenotypes susceptible to hormone and epigenetic interaction that will aid in our understanding of the molecular pathology of PPD and hold the potential to act as novel and modifiable therapeutic targets.

描述(由申请人提供)：这是一种应用程序，使用我们开发的一种新的表观遗传学生物标记物来实施产后抑郁症(PPD)的血液筛查，从而能够在产后风险个体和匹配的对照组中纵向评估PPD特定的神经成像表型。该项目将利用女性精神健康和产后抑郁领域的领先者、经验丰富的DNA甲基化和生物标记物研究人员以及有成就的神经成像师的才华。通过最近一项跨物种的转换实验，研究了PPD高危女性的海马区对雌激素和表观基因组图谱的表观遗传反应，我们确定了一组在功能上与调节突触可塑性相关的表观遗传学标记，并能够以85%的准确率预测PPD。我们的结果表明，PPD的风险是由对雌激素的敏感性增加所介导的。外周生物标记物的可获得性为在产后抑郁人群中进行成像表观遗传学打开了新的机会。虽然MDD和PPD的特定神经影像表型有一定的一致性，但目前尚不清楚这些发现是否代表疾病病因或抑郁状态，需要对自发性和既往确诊的情绪障碍病例进行纵向研究才能阐明。中心假设是，PPD的风险可能是由于性腺激素反应的表观遗传重编程机制的敏感性改变而引起的，外围测量的这些基因座的表观遗传变异将与纵向进行性抑郁症相关的神经成像表型相关，包括静息状态、皮质边缘通路的功能连通性改变、情绪处理、工作记忆和产后海马区特定活动的变化。在目标1中，我们将使用标准的妊娠晚期抽血来进行产后抑郁预测，并从普通人群和既往有情绪障碍病史的妇女中产生产后抑郁的风险妇女样本。在目标2中，我们将进行一系列的功能磁共振成像测试，以评估在抑郁前的两周时间点和在重大抑郁发作期间的六周的静息状态功能连通性、情绪反应、工作记忆和海马区特异性的改变。组内比较将确定与目标3中的表观遗传学、血清激素和心理数据相结合的特征相关的内表型。所进行的分析将确定对激素和表观遗传学相互作用敏感的新的脑内表型，这将有助于我们理解PPD的分子病理学，并具有作为新的和可修改的治疗靶点的潜力。