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.

项目摘要创伤后应激障碍（PTSD）是一种常见的，使人衰弱的疾病，暴露于创伤事件。 PTSD经常被诊断不足和处理不足，dospite早期检测和治疗有利的结果。更好地识别障碍敏感性或韧性元素对迅速提供护理以减轻伯恩的疾病。正如PTSD所证明的那样，这是一种流行的理论疾病的敏感性是遗传性的。大规模基因组宽结合研究（GWAS）揭示了一个估计的单核苷酸多态性（SNP）基于5-20％。然而，环境因素，这样作为童年创伤，也已证明可以独立预测PTSD的发展。全基因组整合与PTSD相关的遗传基因座的压力暴露可能会通过环境相互作用来阐明基因影响障碍的敏感性。在此提案中，我将通过联合遗传和环境调查基因座采用综合多级方法来检查和验证大脑区域的PTSD风险的贡献和特定于细胞类型的调节。将GWAS调查结果与环境暴露相结合的一个主要问题是 GWAS识别的语言环境的主要非编码性质，掩盖了清晰的功能分析。为了克服这一点，我将将确定的变体与附近的表达变化相关联，以发现近端或不同的调节基因靶标。具有转录组调节活性的这种变体称为表达定量性状基因座（eqtls）。由于转录组调控与上下文有关，因此EQTL在遗传和环境上捕获调节表达，使其可用于破译PTSD的基因组调节。我进行了初步从背外侧前额外皮质（DLPFC）中验证验证后脑部样本中的EQTL搜索，证明在暴露于创伤的人群的大脑中可以检测到应力相互作用eqTL。在AIM 1中，我将扩展此分析除了内侧杏仁核的DLPFC之外，还可以发现遗传应激反应的调节景观整个大脑。在AIM 2中，我将检查这些变体的热量，以证明压力依赖性调节。我已经开发了一种捕获PTSD特异性应力反应的体外模型。在此模型中，候选效应器变体将受到质疑，以影响影响疾病生物学的下游效应。这将通过大规模CRISPR筛选方法的培训和下游收敛的计算探测途径。这项工作将在西奈山（ISMMS）和耶鲁大学的伊坎医学院内进行大学目前分别排名第11和第10位，分别在美国最好的研究中。在遗传学和神经科学部门之间，我得到了超过100,000 ft2的研究除了超过2亿美元的科学计算，计划和4500 ft2的机构核心设施资源。共同利用了我的机构的资源以及我共同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）专业发展和奖学金，（3）精通，领导力和倡导，（4）和临床研究整合。