Neuroimaging epigenetics of prospective postpartum depression biomarkers

描述（由申请人提供）：这是一项使用我们开发的新型表观遗传生物标志物对产后抑郁症（PPD）进行血液筛查的申请，可以对有风险的个体和匹配的对照组进行产后PPD特异性神经影像学表型的纵向评估。该项目将利用女性心理健康和产后抑郁症领域的一位领导者、一位经验丰富的DNA甲基化和生物标志物研究人员以及一位有成就的神经成像专家的才能。通过最近的一项跨物种翻译实验，研究了PPD风险女性的前瞻性样本中海马对雌激素的表观遗传反应和表观基因组分析，我们发现了一组与突触可塑性调节功能相关的表观遗传标记，能够以bb0 85%的准确率预测PPD。我们的研究结果表明，PPD的风险是由对雌激素的敏感性增加介导的。外周生物标志物的可用性为在PPD人群中进行成像表观遗传学提供了新的机会。虽然在MDD和PPD特异性神经影像学表型之间存在一些一致性，但尚不清楚这些发现是否代表疾病病因或抑郁状态，并且需要对自发性和既往情绪障碍诊断病例进行纵向研究来阐明。中心假设是PPD风险可能是由于对性腺激素反应的表观遗传重编程机制的敏感性改变而产生的，并且这些位点的外周测量的表观遗传变异将与纵向进行性抑郁症相关的神经影像学表型相关，包括静息状态皮质边缘通路的功能连接改变，情绪处理，工作记忆，产后海马亚区特异性活动的变化。在目标1中，我们将使用标准的妊娠晚期抽血来进行PPD预测，并从普通人群和有情绪障碍病史的女性中产生PPD风险女性样本。在Aim 2中，我们将进行一系列fMRI测试，以评估静息状态功能连通性、情绪反应、工作记忆和海马亚区特异性改变，这些变化分别发生在抑郁前两周和重度抑郁发作期间的六周。在目标3中，组内比较将确定与表观遗传、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易受激素和表观遗传相互作用影响的新型脑内表型，这将有助于我们理解PPD的分子病理学，并有可能作为新的和可修改的治疗靶点。

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.