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病学的复杂多基因风险架构 神经发育障碍。大多数与疾病相关的常见变体是非编码的。候选风险基因座 在非编码区域中，通常是调节元素，例如增强子和启动子，可能会调节 关键基因的转录活性有助于一种或多种内表型。功能影响的影响 大多数与疾病相关的非编码变体仍然未知。已知增强剂是细胞类型的基础 基因表达的特定模式影响细胞发育和对环境的反应 状况。与遗传风险相关的候选调节序列（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标。在过去的十年中，大规模 监管序列​​的识别已经扩大了我们的意识，并强调了它们的重要性 在有意义的规模上的调节元素的功能表征仍然无法访问。只有 高通量测序和大规模筛选技术的当代进步，例如 大规模平行的记者测定法（MPRA）表征了不断增长的非编码风险基因座的清单 马斯变得可行。我将在HIPSC衍生的脑细胞中应用MPRA来识别精神病风险变体 在表现出细胞类型特异性转录活性的CR中。此外，在互动中i Wi/1 lool < 产前压力和炎症，并具有遗传性risl <以及因此对心理健康负面影响的敏感性 后来生活。有足够的证据将胎儿环境因素与神经发育相关联 轨迹。怀孕期间的压力或炎症与心理健康结局有关 后代。产前环境因素对脑相关CRS的影响可能解释与 母体免疫激活（MIA）以及增加对压力和负面健康轨迹的敏感性 后代。 MIA潜在的生物学机制可能会导致这种易感性提高。使用mpras， 我将确定与大脑相关的CR中的风险变异，以使更敏感或韧性具有更大的敏感性或弹性 环境压力源。通过评估开发过程中的环境互动，我们将研究 对后来生活创伤经历或症状表现之前的风险的贡献。这项研究会 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资金中排名全国第二。将近5,000 ft2的空间分配给培训计划 在神经科学系和弗里德曼脑研究所内。此外，还有约100,000 ft2 容纳该部门和LNSTITUTE的研究计划，以及专门用于机构核心的4,500 FT2 设施。该奖学金将支持我成为多学科的翻译校长的旅程 研究人员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。