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.

我们建议研究心理个体差异背后的分子机制 幸福感（PWB）是一个多维结构，包括积极情绪、生活满意度、 以及生活的目的感和意义，并且不仅仅是没有负面情绪状态。 前瞻性纵向研究表明，PWB 与更好的身心健康相关 事实上，在调整负面情绪和其他相关混杂因素后，PWB 降低了风险。 有自杀意念、抑郁症、药物滥用、创伤后应激障碍、阿尔茨海默氏痴呆症、 心脏病、糖尿病可降低全因死亡率。 值得注意的是，PWB 具有显着的遗传贡献，遗传力约为 64%。 然而，尽管 PWB 有许多重要的益处，但其遗传机制在很大程度上仍不清楚。 为了解决这个问题，我们最近进行了一项积极情绪的全基因组关联研究（GWAS），这是一个主要的 我们发现了一个单核苷酸多态性（SNP），rs322931，与显着相关。 此后，这种关联在全基因组水平上被复制到了两个独立的个体中。 我们随后发现 rs322931 是一个顺式表达性状基因座（eQTL 定量）。 microRNA 181a 和 181b (miR-181a/b) 在人类血液和大脑中表达。 丰富的奖励激励神经回路并调节突触可塑性和免疫功能 综上所述，我们确信 miR-181a/b 在 PWB 中发挥着作用。 鉴于这些令人兴奋的数据，我们建议利用已经收集的数据来验证和扩展我们的发现 人类死后大脑转录组、表观基因组、蛋白质组和基因组数据，以阐明分子生物学 PWB 的机制。这个独特的 675 个人脑数据集，由 NIH 资助的 Rush 收集。 记忆与衰老项目 (MAP) 历经 20 年，为研究记忆与衰老机制提供了难得的机会 相关器官（即人脑）中的 PWB 对于我们提出的分析具有 90% 的功效。 为此，我们提出以下目标：验证 GWAS 的遗传发现。 2040 年退伍军人和 MAP 参与者的积极情绪将通过调查来扩展我们的发现。 使用假设驱动和假设中立的方法研究大脑 microRNA 在 PWB 中的贡献。 值得注意的是，microRNA 是基因表达的重要转录后调节因子，并且共同作用 Aim 3 将采用创新的系统生物学来调节一半以上的蛋白质编码基因。 识别基因网络和 PWB 关键表达调控驱动因素的方法，以及确定 PWB 中它们的蛋白质水平是否相应改变。 总之，这项新颖且创新的提案利用了之前收集的退伍军人基因样本 以及来自 NIH 资助的 MAP 队列的人类死后大脑“组学”数据 我们计划将这些数据与我们将生成的数据结合起来，并以创新的方式进行分析。 我们希望利用系统生物学方法来阐明 PWB 的分子机制。 PWB 架构有助于未来开发基于生物标志物的风险筛查 分层和干预以增强工作计划和预算及其有益效果。