Reproductive Endocrine Related Mood Disorders-Differential Sensitivity

生殖内分泌相关情绪障碍-敏感性差异

基本信息

批准号：
10929821
负责人：
Peter Schmidt
金额：
$ 67.45万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929821
关键词：
Accounting Address Affective Affective Symptoms Allopregnanolone Amygdaloid structure Anxiety Appearance Behavior Behavioral Biological Brain Brain region Breast Cell Line Cell Nucleus Cell model Cellular Stress Central Nervous System Characteristics Child Childbirth Chronic Disease Classification Clinical Clinical Management Clinical Protocols Clinical Research Clinical Trials Collaborations DNA DNA Methylation Data Data Set Depressed mood Development Diagnostic Direct Costs Disease Disparity Down-Regulation Endocrine Equipment and supply inventories Estradiol Event Exposure to Facilities and Administrative Costs Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Genotype Glucocorticoids Health Hormonal Hormone imbalance Hormone secretion Hormone use Hormones Hour Human Hypothyroidism In Vitro Infant Infanticide Intervention Longevity Machine Learning Major Depressive Disorder Medial Mediator Menstrual cycle Mental Depression Mental disorders Methods Modeling Molecular Molecular Target Mood Disorders Moods Morbidity - disease rate Mothers National Institute on Alcohol Abuse and Alcoholism Nature Neurons Ovarian Ovarian hormone Pain Patients Pattern Perimenopause Phenotype Physiological Postpartum Depression Postpartum Period Predisposition Prefrontal Cortex Pregnancy Premenstrual syndrome Procedures Progesterone Psychoses Rare Diseases Recurrence Reporting Reproductive Periods Research Risk Role Sampling Sex Differences Signal Transduction Source Specificity Steroid Receptors Steroids Stimulus Suicide Symptoms System Techniques Testing Transcript Transgenic Mice Variant Woman Work analysis pipeline behavioral health behavioral phenotyping behavioral response burden of illness cell type clinical diagnosis cognitive function comorbidity comparison control depressive symptoms desensitization differential expression food craving hormone sensitivity hormone therapy in vivo induced pluripotent stem cell innovation interest lymphoblastoid cell line metabolome metabolomics mortality mouse model multimodal neuroimaging neural neuroregulation neurosteroids novel novel therapeutics physical symptom premenstrual dysphoric disorder reproductive reproductive hormone response steroid hormone transcriptome sequencing transcriptomics

项目摘要

This report includes work arising from the following clinical protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481. The studies conducted within this project are relevant to our understanding of womens behavioral health, sex differences in psychiatric illness and the course of affective disorders in general. The innovation in our work is both conceptual as well as applied. In the past, RMDs were considered to be hormone excess or deficiency states, prompting treatments to correct these inferred hormonal imbalances. We address critical mechanistic questions about the role of reproductive hormones on brain function and behavior in RMDs. We employ steroid receptor modulators to isolate and characterize the effects of specific steroids on behavior in both women with RMDs and well-characterized asymptomatic controls. These clinical studies have demonstrated that a change in steroid hormone secretion induces affective symptoms in most women clinically diagnosed with RMDs, but the identical hormonal intervention has no effect on mood/behavior in asymptomatic controls. Thus, our work has reframed the understanding of these conditions from hormonal excess or deficiency states to that of ovarian steroid-sensitive behavioral states. We also employ both multimodal neuroimaging studies and in vitro cellular models to investigate the physiologic basis of the hormone sensitive phenotype in RMDs. We have characterized neuronal hubs that are differentially regulated by ovarian steroids in women with RMDs, developed a steroid metabolomics platform to examine the steroid metabolome in PMDD, demonstrated an impact of genotypic variation in steroid-regulated genes on the central nervous system (CNS) response to steroids (in a brain region-specific manner), and identified underlying cellular mechanisms for the alterations in steroid signaling in both PMDD and PPD (the mechanisms underlying several of which are being actively pursued). These findings are unique and serve to inform our understanding of the pathophysiology of these conditions and their potential comorbidities, their clinical management and use of hormone therapies. Finally, having developed and tested these methods in women with RMDs, we will employ these techniques in our new studies of postpartum psychosis a condition potentially lethal to both mother and child. Findings to date include: 1) the differential affective and behavioral response to normal physiologic events in women with PMDD compared with control women a behavioral phenotype in which we have explored the underlying biologic risks. We now have replicated these findings which were originally reported in a relatively small sample (i.e., ten women with PMDD and fifteen controls) now in much larger samples of women with PMDD (n=34) and controls (n=76). We found the identical phenomenon of mood destabilization after exposure to physiologic levels of either estradiol or progesterone in women with PMDD, but no effect of hormonal exposure in asymptomatic control women. Interestingly, the symptom of irritabilitys recurrence in PMDD was more related to progesterone exposure (and therefore neurosteroid) than to estradiol exposure. Additionally, physical symptoms of breast pain, bloating and food cravings showed a similar pattern of hormone-triggered recurrence in PMDD but with more specificity (e.g., breast pain only appeared after exposure to estradiol). 2) We employ a machine learning platform in a large sample of over 800 women (women who met DSM criteria for PMDD, asymptomatic controls and women who presented with PMDD but who did not meet research criteria for PMDD) who completed daily symptom ratings of sadness, anxiety and irritability across at least two menstrual cycles. We will examine several questions in this data set including the specificity of the symptom of irritability in PMDD, the clinical characteristics associated with PMDD (versus those who do not meet criteria for PMDD) and whether there are distinct patterns of symptom expression that define specific phenotypes of PMDD that will be employed with other ongoing studies (e.g., development of polygenic scores) to better characterize this condition. 3) In collaboration with Dr. David Goldman at NIAAA, we developed lymphoblastoid cell lines (LCLs) and human induced-pluripotent cell lines (h-IPSCs) from women with and without RMDs (i.e., women with PMDD, PPD, PPP and perimenopausal depression PMD). In LCLs from women with and without PPD, we observed that PPD LCLs had an intrinsic downregulation of transcript expression, with the greatest disparity between PPD cases and controls in differentially expressed genes during in vitro exposure to supraphysiologic levels of estradiol and progesterone (mimicking exposures during pregnancy). The top genes significantly decreased in PPD, (IMPACT, a translational regulator of cellular stress conditions, and WWTR1, a homeostatic mediator of transcription) suggest novel possible molecular targets underlying in vivo findings such as increased DNA methylation and desensitization of the glucocorticoid system in women who develop PPD compared to controls. Additionally, given the documented benefits of brexanolone (allopregnanolone ALLO) in PPD we examined the effects of ALLO on gene expression in cell lines from PPD and controls. In this study, gene expression in LCLs were studied after 60-hours of ALLO exposure. The major finding was that in LCLs from women with PPD (compared with their baseline expression), ALLO induced 2 fold fewer differentially expressed genes compared with gene expression within LCLs from matched controls. This suggests ALLO's potential to induce divergent cellular responses depending upon genetic (or diagnostic) background. These finding are currently being explored in ongoing studies examining the molecular and transcriptomic consequences of ALLO signaling within the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) in PPD, and which specific cell types are involved in this signaling (by employing single nucleus sequencing procedures). Finally, we explore how these changes in gene expression differ across species using transgenic mouse models of PPD and patient-derived LCL models for PPD and controls. We also are examining characteristics of the phenotype of differential ovarian hormone sensitivity across all RMDs, how genes and transcripts compare across disorders, and to non-endocrine related mood disorders such as depression. We are currently managing the inventory, organization, and development of a major genotyping project involving DNA samples and cell lines spanning 30 years across multiple RMDs - some 500 samples have been identified and physically located, with over 150 of these now genotyped utilizing the global diversity array, a chip with over 1.8 million SNPs of interest. These SNPs will be used to calculate polygenic scores for multiple phenotypes of interest. Finally, we have collected Ampliseq RNA-seq data on PMDD, PMD, PPD, and PPP at baseline, and we are currently devising an analysis pipeline to assess the intrinsic similarities and differences across these disorders and compared to controls.

该报告包括由以下临床方案产生的工作：NCT00005011，NCT00056901，NCT00059228，NCT00082043，NCT00100360，NCT00001177，NCT0000001259和NCT0000001481。该项目中进行的研究与我们对女性行为健康的理解，精神疾病的性别差异以及一般的情感障碍过程有关。我们工作的创新既是概念性的，也是应用的。过去，RMD被认为是激素过量或缺乏状态，促使治疗纠正这些推断的激素失衡。我们解决了有关生殖激素对RMD中脑功能和行为的作用的关键机理问题。我们采用类固醇受体调节剂来隔离和表征特定类固醇对RMD和充分表征无症状对照的女性行为的影响。这些临床研究表明，类固醇激素分泌的变化会引起大多数被临床诊断为RMD的女性的情感症状，但是相同的激素干预对无症状控制中的情绪/行为没有影响。因此，我们的工作将对这些条件的理解从激素过剩或缺乏状态转化为卵巢类固醇敏感的行为状态。我们还采用了多模式神经影像学研究和体外细胞模型来研究RMD中激素敏感表型的生理基础。我们表征了神经元中心的神经元枢纽，这些神经元中受卵巢类固醇在RMD的妇女中的调节，开发了一种类固醇代谢组学平台，以检查PMDD中类固醇的代谢组，证明了基因型变异在类固醇受调的基因对中枢神经系统（中枢神经系统（CN）响应（在脑区域）响应（脑区域）的影响（脑区域）的影响（脑区域），并鉴定出脑区域性的核心（识别），并鉴定出较大的核心范围。 PMDD和PPD的信号传导（其中几种正在积极追求的机制）。这些发现是独一无二的，有助于我们了解这些疾病的病理生理及其潜在合并症，临床管理和激素疗法的使用。最后，在RMD的女性中开发并测试了这些方法后，我们将在新的对产后精神病的新研究中采用这些技术，是母亲和儿童可能致命的疾病。迄今为止的发现包括：1）与对照妇女相比，PMDD女性正常生理事件的差异情感和行为反应是一种行为表型，我们探索了潜在的生物学风险。现在，我们已经复制了这些发现，这些发现最初是在相对较小的样本（即10个具有PMDD和15个对照的女性）中报道的，现在有PMDD（n = 34）和对照组（n = 76）的较大女性样本中。我们发现PMDD女性的雌二醇或孕酮的生理水平后，情绪不稳定的现象相同，但无症状对照女性没有激素暴露的影响。有趣的是，PMDD易怒复发的症状与孕酮暴露（因此是神经类固醇）更重要，而不是与雌二醇暴露有关。此外，乳房疼痛，腹胀和食物渴望的身体症状表现出类似的PMDD激素触发复发模式，但具有更特异性（例如，仅在暴露于雌二醇后才出现乳房疼痛）。 2）我们在大量的800多名女性（符合PMDD的DSM标准，无症状对照和与PMDD呈现的妇女但不符合PMDD的研究标准的女性）中采用机器学习平台，这些妇女至少符合PMDD的研究标准，这些妇女至少符合PMDD的研究标准。我们将研究该数据集中的几个问题，包括PMDD中易怒的症状的特异性，与PMDD相关的临床特征（与不符合PMDD标准的人有关）以及是否存在定义PMDD的特定表达的不同模式，这些模式是否会用于PMDD的特定表达，这些表达将用于其他正在进行的研究（例如，开发的条件）。 3）与NIAAA的David Goldman博士合作，我们开发了有和没有RMD的妇女（即患有PMDD，PPD，PPD，PPP和近视抑郁症PMD的女性）的妇女（即患有RMD的妇女）的淋巴细胞细胞系（LCLS）和人类诱导的诱导细胞系（H-IPSC）。在患有和没有PPD的女性的LCL中，我们观察到PPD LCLS的内在下调转录表达，PPD病例的差异和对照在体外表达基因的对照之间的差异最大，但在体外暴露于超X. X.超X. X.超X. X.超X. X.超生型雌激素水平的雌二醇和孕激素（模仿怀孕期间）。 PPD中的顶部基因显着降低（影响，是细胞应激条件的翻译调节剂，以及WWTR1，一种转录的稳态介质）表明，体内发现的新型可能的分子靶标，例如增加了DNA甲基化和与对照组相比的女性葡萄糖皮质激素的脱糖尿类动物的脱糖尿类动物。此外，鉴于PPD中Brexanolone（Allopregnanolone allo）的记录益处，我们检查了Allo对PPD和对照细胞系中基因表达的影响。在这项研究中，在经过60小时的Allo暴露后，研究了LCL中的基因表达。主要发现是，在具有PPD女性的LCL中（与基线表达相比），与来自匹配的对照组的LCL相比，Allo诱导了2倍差异表达的基因。这表明Allo根据遗传（或诊断）背景诱导分歧的细胞反应的潜力。目前正在正在进行的研究中探讨了这些发现，研究了PPD中基底外侧杏仁核（BLA）和内侧前额叶皮层（MPFC）中Allo信号传导的分子和转录组后果，以及该信号中哪些特定细胞类型（通过采用单核测序程序）。最后，我们使用PPD的转基因小鼠模型和PPD和对照的患者衍生的LCL模型探索了基因表达的这些变化在物种之间如何差异。我们还正在研究所有RMD的差异卵巢激素灵敏度的表型的特征，基因和转录本如何比较跨疾病的基因和转录，以及与抑郁症等非分泌有关的情绪障碍。目前，我们正在管理一个主要的基因分型项目的库存，组织和开发，该项目涉及多个RMD的DNA样品和细胞系跨越30年的细胞系 - 已经确定了500个样品并物理位置，其中有150多个使用全球多样性阵列的基因型，这是一个超过1800万个SNP的芯片。这些SNP将用于计算多种感兴趣表型的多基因评分。最后，我们在基线时收集了有关PMDD，PMD，PPD和PPP的Ampliseq RNA-Seq数据，目前我们正在设计分析管道，以评估这些疾病之间的固有相似性和差异并与对照组相比。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics.

通过日常情绪评级动态预测患有经前焦虑症的女性对亮丙瑞林的反应。

DOI：
10.1016/j.jpsychires.2010.07.006
发表时间：
2011
期刊：
Journal of psychiatric research
影响因子：
4.8
作者：
Pincus,StevenM;Alam,Shaista;Rubinow,DavidR;Bhuvaneswar,ChayaG;Schmidt,PeterJ
通讯作者：
Schmidt,PeterJ

Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study.

DOI：
10.1176/appi.ajp.2012.12030385
发表时间：
2013-03
期刊：
The American journal of psychiatry
影响因子：
0
作者：
Baller EB;Wei SM;Kohn PD;Rubinow DR;Alarcón G;Schmidt PJ;Berman KF
通讯作者：
Berman KF

Rapid response to fluoxetine in women with premenstrual dysphoric disorder.

DOI：
10.1002/da.21959
发表时间：
2012-06
期刊：
DEPRESSION AND ANXIETY
影响因子：
7.4
作者：
Steinberg, Emma M.;Cardoso, Graca M. P.;Martinez, Pedro E.;Rubinow, David R.;Schmidt, Peter J.
通讯作者：
Schmidt, Peter J.

Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study.

DOI：
10.1007/s00737-019-00991-3
发表时间：
2020-06
期刊：
ARCHIVES OF WOMENS MENTAL HEALTH
影响因子：
4.5
作者：
Li, Howard J.;Martinez, Pedro E.;Li, Xiaobai;Schenkel, Linda A.;Nieman, Lynnette;Rubinow, David;Schmidt, Peter J.
通讯作者：
Schmidt, Peter J.

Estrogen receptor alpha (ESR-1) associations with psychological traits in women with PMDD and controls.