Massively Parallel Characterization of Cell-type and Context Specific Regulatory Risk Elements Across Psychiatric Disorders in a Stem Cell Model of Neurodevelopment

神经发育干细胞模型中精神疾病细胞类型和背景特定监管风险因素的大规模并行表征

• 批准号: 10610724
• 负责人: Kayla Townsley
• 金额: $ 4.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2025-04-10
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610724
• 关键词: Adult; Affect; Anorexia Nervosa; Anxiety Disorders; Architecture; Area; Astrocytes; Atlases; Attention Deficit Disorder; Awareness; Biological; Biological Assay; Bipolar Disorder; Brain; Brain Diseases; Child; Complex; Core Facility; Cues; Data; Data Analyses; Data Set; Dedications; Development; Diagnostic; Disease; Distal; Dorsal; Dose; Drug usage; Elderly; Elements; Enhancers; Environment; Environmental Risk Factor; Fellowship; Fetal Development; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Risk; Genetic Transcription; Genomics; Glutamates; Goals; Health; Heritability; High-Throughput Nucleotide Sequencing; Human; Hydrocortisone; In Vitro; Inflammation; Inflammatory; Institution; Interleukin-6; Lateral; Leadership; Libraries; Life; Link; Logic; Major Depressive Disorder; Medical; Mental Health; Mental disorders; Mind; Modeling; Molecular; Mutagenesis; Neurodevelopmental Disorder; Neurons; Neurosciences; Neurotic Disorders; Outcome; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Pregnancy; Principal Investigator; Regulatory Element; Reporter; Research; Risk; Schizophrenia; Scholarship; Stress; Symptoms; TNF gene; Techniques; Testing; Therapeutic Intervention; Toxic effect; Training; Training Programs; Translating; United States; United States National Institutes of Health; Untranslated RNA; Variant; Work; adverse childhood events; appropriate dose; autism spectrum disorder; brain cell; causal variant; cell type; cellular development; clinical predictors; disorder risk; early childhood; endophenotype; environmental stressor; experience; fetal; genetic disorder diagnosis; genetic variant; immune activation; improved; in silico; in vitro activity; induced pluripotent stem cell; insight; interest; multidisciplinary; neurodevelopment; neuropsychiatric disorder; novel; novel therapeutic intervention; offspring; postnatal; prenatal; prenatal influence; prenatal stress; programs; promoter; resilience; response; risk variant; screening; stem cell model; therapeutic target; trait; transcriptome sequencing; transcriptomics; translational impact; translational potential

There is an urgent need to decipher the complex polygenic risk architecture of neuropsychiatric and neurodevelopmental disorders. Most disease-associated common variants are non-coding. Candidate risk loci in noncoding regions are often regulatory elements, such as enhancers and promoters, that may modulate transcriptional activity of key genes contributing to one or many endophenotypes. The functional impact of most disease-associated non-coding variants remains unknown. Enhancers are known to underlie cell-type specific patterning of gene expression influencing cellular development and responses to environmental conditions. Candidate regulatory sequences (CRS) associated with genetic risk are likely key drivers of underlying endophenotypes and represent potential therapeutic targets. Over the past decade, large-scale identification of regulatory sequences has expanded our awareness and highlighted their importance yet functional characterization of regulatory elements on a meaningful scale remained inaccessible. Only with contemporary advances in high-throughput sequencing and large-scale screening techniques, such as the Massively Parallel Reporter Assay (MPRA), has characterizing the growing list of non-coding risk loci en masse become feasible. I will apply a MPRA in hiPSC-derived brain cells to identify psychiatric risk variants within CRS that demonstrate cell-type specific transcriptional activity. Additionally, I wi/1 lool< at the interactions ol pre-natal stress and inflammation with genetic risl< and consequent susceptibility to negative mental health later in life. There is sufficient evidence correlating fetal environmental factors with neurodevelopmental trajectories. Stress or inflammation during pregnancy has been linked to mental health outcomes in the offspring. The influence of pre-natal environmental factors on brain-related CRSs may explain correlations with Maternal-Immune Activation (MIA) and increased susceptibility to stress and negative health trajectories of the offspring. Biological mechanisms underlying MIA may contribute to this increased susceptibility. Using MPRAs, I will identify risk variants within brain-related CRS that confer greater susceptibility, or resilience, to environmental stressors. By assessing environmental interactions during development, we will look at contributions to risk that precede later-life traumatic experiences or symptom presentations. This research will take place under the Mount Sinai Neuroscience Training Program. Mount Sinai's Department of Neuroscience currently ranks 2nd nationally in NIH funding. Nearly 5,000 ft2 of space are allocated to the Training Program within the Neuroscience Department and Friedman Brain Institute. There is, additionally, ~100,000 ft2 that house the Department's and the lnstitute's research programs and 4,500 ft2 dedicated to Institutional CORE facilities. This fellowship would support my journey to become a multidisciplinary, translational principal investigator by providing training in four major areas: Scientific Excellence. Scientific Alliance. Academic Scholarship. and Scientific Leadership.

迫切需要破译神经精神和精神疾病复杂的多基因风险结构。 神经发育障碍。大多数与疾病相关的常见变异都是非编码的。候选风险位点 非编码区域通常是调节元件，例如增强子和启动子，它们可能调节 有助于一种或多种内表型的关键基因的转录活性。功能影响 大多数与疾病相关的非编码变异仍然未知。已知增强子是细胞类型的基础 影响细胞发育和对环境反应的基因表达的特定模式 状况。与遗传风险相关的候选调控序列（CRS）可能是关键驱动因素 潜在的内表型并代表潜在的治疗靶点。近十年来，大规模 调控序列的识别扩大了我们的认识并强调了它们的重要性 仍无法在有意义的范围内对监管要素进行功能表征。仅与 现代高通量测序和大规模筛选技术的进步，例如 大规模并行报告基因检测 (MPRA) 描述了不断增长的非编码风险位点列表 大众变得可行。我将在 hiPSC 衍生的脑细胞中应用 MPRA 来识别精神病风险变异 CRS 内的细胞类型特异性转录活性。此外，我 wi/1 关注互动 ol 产前压力和炎症与遗传风险以及随之而来的负面心理健康的易感性 在以后的生活中。有足够的证据表明胎儿环境因素与神经发育相关 轨迹。怀孕期间的压力或炎症与心理健康结果有关 后代。产前环境因素对大脑相关 CRS 的影响可以解释与 母体免疫激活（MIA）以及对压力和负面健康轨迹的敏感性增加 后代。 MIA 的生物学机制可能导致这种易感性增加。使用 MPRA， 我将识别与大脑相关的 CRS 中的风险变异，这些变异赋予了更大的易感性或弹性， 环境压力源。通过评估开发过程中的环境相互作用，我们将着眼于 在晚年创伤经历或症状出现之前对风险的贡献。这项研究将 在西奈山神经科学培训计划下进行。西奈山神经科学系 目前在 NIH 资助中排名全国第二。近 5,000 平方英尺的空间被分配给培训计划 神经科学系和弗里德曼脑研究所。此外，还有约 100,000 平方英尺 容纳部门和研究所的研究项目，并拥有 4,500 平方英尺的空间专门用于机构核心 设施。这项奖学金将支持我成为一名多学科、转化校长的旅程 研究者通过在四个主要领域提供培训： 科学卓越。科学联盟。学术的 奖学金。和科学领导力。