Modeling gene x environment interactions in post-traumatic stress disorder.

创伤后应激障碍中基因与环境相互作用的建模。

基本信息

批准号：
10750239
负责人：
Carina Seah
金额：
$ 5.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-26 至 2027-06-25
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750239
关键词：
Advocacy Affect Amygdaloid structure Area Autopsy Biology Blood Brain Brain region CRISPR screen Catalogs Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Complex Core Facility Data Detection Development Diagnosis Disease Distal Early Diagnosis Early Intervention Early treatment Electronic Health Record Elements Environment Environmental Exposure Environmental Risk Factor Etiology Exposure to Fellowship Functional disorder Future Gene Expression Gene Targeting Genes Genetic Genetic Risk Genetic Transcription Genomics Genotype Glossary Goals Heritability Human Hydrocortisone In Vitro Individual Institution Joints Leadership Link Maps Measures Medial Mediating Mentorship Methods Modeling Nature Neurons Neurosciences Outcome Pathway interactions Patient risk Patients Pattern Phenotype Physicians Post-Traumatic Stress Disorders Predisposition Prefrontal Cortex Quantitative Trait Loci Regulation Research Resources Risk Risk Estimate Role Sampling Scholarship Scientist Single Nucleotide Polymorphism Stratification Stress Training Training Support Translating Trauma Traumatic Brain Injury Universities Untranslated RNA Validation Variant Visual Work accurate diagnostics algorithm development biobank biological adaptation to stress biomarker discovery brain cell brain tissue care delivery cell type clinical practice clinical risk clinically relevant cohort computing resources conditioned fear disorder risk experimental study gene environment interaction gene interaction genetic element genetic variant genome wide association study genome-wide genomic locus improved in vitro Model medical schools novel outcome prediction patient stratification pediatric trauma personalized medicine phenome physiologic model programs resilience risk prediction risk stratification risk variant scientific computing single-cell RNA sequencing statistics theories transcriptomics translational impact translational potential trauma exposure traumatic event variant detection

项目摘要

PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a common, debilitating disorder, triggered by exposure to a traumatic event. PTSD is often under-diagnosed and undertreated, despite early detection and treatment governing favorable outcomes. Better identification of elements of disorder susceptibility or resilience is important for prompt delivery of care to mitigate disorder burden. As PTSD has shown to be heritable, a prevailing theory of disorder susceptibility is genetic. Large-scale genome wide association studies (GWAS) have revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of 5-20%. Yet, environmental factors, such as childhood trauma, have also shown to independently predict PTSD development. Genome-wide integration of PTSD-associated genetic loci with stressful exposures may elucidate gene by environment interactions that influence disorder susceptibility. In this proposal, I will investigate loci with joint genetic and environmental contributions to PTSD risk, employing an integrative multi-level approach to examine and validate brain region and cell type-specific regulation. One major issue integrating GWAS findings with environmental exposures is the largely non-coding nature of GWAS-identified loci, obscuring clear functional ramifications. To overcome this, I will associate identified variants with nearby expression changes to uncover regulation of proximal or distal gene targets. Such variants with transcriptomic regulatory activity are termed expression quantitative trait loci (eQTLs). As transcriptomic regulation is context-dependent, eQTLs capture genetically and environmentally regulated expression, making them useful for deciphering genomic regulation of PTSD. I performed a preliminary eQTL search in post-mortem brain samples from the dorsolateral pre-frontal cortex (DLPFC), demonstrating that stress-interactive eQTLs are detectable in brains of trauma-exposed cohorts. In Aim 1, I will extend this analysis beyond the DLPFC to the medial amygdala, to uncover the regulatory landscape of genetic stress response across the brain. In Aim 2, I will examine causality of these variants to demonstrate stress-dependent regulation. I have developed an in vitro model capturing PTSD-specific stress response. In this model, candidate effector variants will be interrogated for downstream effects impacting disorder biology. This will be accomplished via training in large scale CRISPR-screening methods and in computational probing of convergent downstream pathways. This work will take place within the Icahn School of Medicine at Mount Sinai (ISMMS) and Yale University, currently ranked #11 and #10 among the nation’s best medical schools for research, respectively. Between the Departments of Genetics and Neuroscience, I am supported by over 100,000 ft2 of research programs and 4500 ft2 of institutional core facilities, in addition to over $200 million in scientific computing resources. Together, this fellowship leverages the resources of my institutional and the expertise of my co- sponsors to support my training in four major areas: (1) Scientific excellence, (2) professional development and scholarship, (3) mentorship, leadership, and advocacy, (4) and clinical-research integration.

项目概要创伤后应激障碍 (PTSD) 是一种常见的、使人衰弱的疾病，由暴露于创伤性事件引发尽管早期发现和治疗有效，但创伤后应激障碍 (PTSD) 的诊断和治疗往往不足。更好地识别疾病易感性或恢复力的因素对于获得良好的结果非常重要。由于创伤后应激障碍（PTSD）已被证明是可遗传的，这是一种流行的理论。大规模基因组关联研究（GWAS）揭示了疾病易感性是遗传性的。估计基于单核苷酸多态性 (SNP) 的遗传力为 5-20%，然而，环境因素等。与童年创伤一样，也被证明可以独立预测 PTSD 的全基因组整合。与应激暴露相关的 PTSD 相关基因位点可能通过环境相互作用来阐明基因在本提案中，我将研究遗传和环境联合的基因座。采用综合多层次方法检查和验证大脑区域对 PTSD 风险的贡献将 GWAS 研究结果与环境暴露相结合的一个主要问题是 GWAS 识别的基因座基本上是非编码性质，掩盖了明确的功能后果。我将把识别出的变异与附近的表达变化联系起来，以揭示近端或远端的调节具有转录组调控活性的此类变体被称为表达数量性状基因座。 (eQTL) 由于转录组调控是依赖于环境的，因此 eQTL 捕获遗传和环境因素。调节表达，使它们有助于破译 PTSD 的基因组调控。对来自背外侧前额皮质 (DLPFC) 的死后大脑样本进行 eQTL 搜索，证明在目标 1 中，我将扩展此分析。从 DLPFC 到内侧杏仁核，揭示遗传应激反应的调控景观在目标 2 中，我将检查这些变异的因果关系，以证明压力依赖性调节。我开发了一个体外模型，捕捉 PTSD 特异性应激反应，在这个模型中，候选效应器。将询问变异体是否影响疾病生物学的下游效应，这将通过以下方式实现。大规模 CRISPR 筛选方法和聚合下游计算探测的培训这项工作将在西奈山伊坎医学院 (ISMMS) 和耶鲁大学进行。大学目前在全国最好的研究医学院中分别排名第 11 名和第 10 名。在遗传学和神经科学系之间，我得到了超过 100,000 平方英尺的研究支持项目和 4500 平方英尺的机构核心设施，以及超过 2 亿美元的科学计算资金该奖学金共同利用了我所在机构的资源和我同事的专业知识。赞助商支持我在四个主要领域的培训：（1）科学卓越，（2）专业发展和学术，(3) 指导、领导和宣传，(4) 和临床研究整合。