Elucidating molecular mechanisms of psychological well-being

阐明心理健康的分子机制

• 批准号: 10265336
• 负责人: Aliza Pham Wingo
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265336
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Animals; Autopsy; Biological Markers; Blood; Brain; Code; Data; Data Set; Dementia; Diabetes Mellitus; Emotions; Environmental Exposure; Feeling suicidal; Foundations; Funding; Future; Gender; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genetic Transcription; Genotype; Heart; Heart Diseases; Heritability; Human; Immune; Individual; Individual Differences; Intervention; Life; Linear Regressions; Longitudinal prospective study; Measures; Memory; Mental Depression; Mental Health; Messenger RNA; Meta-Analysis; MicroRNAs; Molecular; Motivation; Organ; Participant; Pathway Analysis; Phenotype; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prospective Studies; Proteins; Proteome; Proteomics; Psyche structure; Public Health; Quantitative Trait Loci; Questionnaires; Regulator Genes; Rewards; Risk; Role; Sampling; Single Nucleotide Polymorphism; Substance abuse problem; Suicide; Sum; Synapses; Synaptic plasticity; Systems Biology; Translations; United States National Institutes of Health; Veterans; Well in self; base; cohort; epigenomics; genetic architecture; genetic variant; genome wide association study; genome-wide; genomic data; immune function; innovation; insight; mortality; negative emotional state; neural circuit; novel; phenotypic data; physical conditioning; positive emotional state; protective effect; recruit; relating to nervous system; risk stratification; satisfaction; screening; transcriptomics

We propose to investigate molecular mechanisms that underlie individual differences in psychological well-being (PWB). PWB is a multidimensional construct that encompasses positive emotion, life satisfaction, and sense of purpose and meaning in life, and is more than the absence of negative emotional states. Many prospective longitudinal studies have shown that PWB is associated with better mental and physical health after adjusting for negative emotion and other relevant confounding factors. Indeed, PWB mitigates risks of having suicide ideation, depression, substance abuse, post-traumatic stress disorder, Alzheimer's dementia, heart disease, diabetes, and reduces all-cause mortality. Notably, PWB has a substantial genetic contribution with a heritability of approximately 64%. However, the genetic mechanisms of PWB are largely unknown despite its many important benefits. To address this, we recently performed a genome-wide association study (GWAS) of positive emotion, a major facet of PWB. We found a single nucleotide polymorphism (SNP), rs322931, significantly associated with positive emotion at genome-wide level. This association has since been replicated in two independent datasets. We subsequently found that rs322931 is a cis-expression quantitative trait locus (eQTL) for microRNAs 181a and 181b (miR-181a/b) expressed in human blood and brain. Intriguingly, miR-181a/b are enriched in the reward-motivation neural circuit and regulate synaptic plasticity and immune functioning in animal studies. Taken together, we hypothesize that miR-181a/b play a role in PWB. Given these exciting data, we propose to validate and extend our findings, leveraging already collected human post-mortem brain transcriptomic, epigenomic, proteomic, and genomic data to elucidate molecular mechanisms of PWB. This unique human brain dataset of 675 individuals, gathered by the NIH-funded Rush Memory and Aging Project (MAP) over 20 years, provides a rare opportunity to investigate mechanisms of PWB in the relevant organ, i.e. human brain, with 90% power for our proposed analyses. To that end, we propose the following aims. Aim 1 will validate the genetic findings from our GWAS of positive emotion in 2040 Veterans and MAP participants. Aim 2 will extend our findings by investigating the contribution of brain microRNAs in PWB using both a hypothesis-driven and hypothesis-neutral approach. Notably, microRNAs are important post-transcriptional regulators of gene expression and collectively regulate more than half of the protein-coding genes. Aim 3 will employ innovative systems biology approaches to identify gene networks and key expression regulatory drivers of PWB, as well as determine whether their protein levels are correspondingly altered in PWB. In sum, this novel and innovative proposal capitalizes on previously collected Veteran genetic samples and human post-mortem brain “omic” data from the unique NIH-funded MAP cohort recruited over the last 20 years. We plan to combine these data with the ones we will generate and analyze them with innovative systems biology approaches to elucidate molecular mechanisms of PWB. We aspire to elucidate the genetic architecture of PWB to contribute to future efforts in developing biomarker based screening for risk stratification and intervention to enhance PWB and its beneficial effects.

我们建议研究心理学差异的基础的分子机制 幸福感（PWB）。 PWB是一种多维结构，涵盖积极的情绪，生活满意度， 以及生活中的目标和意义，不仅仅是缺乏负面情绪状态。许多 前瞻性纵向研究表明，PWB与更好的身心健康有关 调整了负面情绪和其他相关的混杂因素之后。确实，PWB降低了 患有自杀的想法，抑郁症，药物滥用，创伤后应激障碍，阿尔茨海默氏症的痴呆症， 心脏病，糖尿病和降低全因死亡率。 值得注意的是，PWB具有大量的遗传贡献，遗传力约为64％。 但是，PWB的遗传机制在很大程度上是未知的目的地，其许多重要的好处。到 解决这个问题，我们最近进行了一项全基因组协会研究（GWAS）的积极情绪，这是一个主要的 PWB的面。我们发现单个核苷酸多态性（SNP），RS322931，与 在全基因组水平上的积极情绪。此后，该关联已在两个独立 数据集。随后，我们发现RS322931是一个用于表达的定量性状基因座（EQTL） MicroRNA 181a和181b（mir-181a/b）在人类的血液和大脑中表达。有趣的是，mir-181a/b是 富含奖励动机神经回路并调节突触可塑性和免疫功能 动物研究。综上所述，我们假设miR-181a/b在PWB中起作用。 鉴于这些令人兴奋的数据，我们建议验证和扩展我们的发现，并利用已经收集的 人类验尸后脑转录组，表观基因组，蛋白质组学和基因组数据阐明分子 PWB的机制。由NIH资助的Rush收集到的675个人的独特人脑数据集 记忆和老化项目（MAP）在20年内，提供了一个难得的机会来调查机制 相关器官（即人脑）中的PWB，我们提出的分析具有90％的功率。 为此，我们提出以下目标。 AIM 1将验证我们的GWA的遗传发现 2040年的退伍军人和地图参与者的积极情绪。 AIM 2将通过调查我们的发现来扩展我们的发现 使用假设驱动和假设与中性方法的PWB中脑microRNA的贡献。 值得注意的是，microRNA是重要的基因表达的转录后调节剂 调节超过一半的蛋白质编码基因。 AIM 3将采用创新系统生物学 识别PWB的基因网络和关键表达调节驱动因素的方法，并确定 它们的蛋白水平是否在PWB中相应改变。 总而言之，这项新颖而创新的提案将资本利用先前收集的资深遗传样本 人类验尸大脑“ OMIC”来自NIH资助的独特地图队列中的“ OMIC”数据 20年。我们计划将这些数据与我们将通过创新的数据结合并分析它们 系统生物学方法阐明了PWB的分子机制。我们渴望阐明遗传 普华永道的建筑为未来开发基于生物标志物筛查的风险做出贡献 分层和干预以增强PWB及其有益效果。