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

迫切需要破译神经精神和精神疾病复杂的多基因风险架构 神经发育障碍。大多数与疾病相关的常见变种都是非编码的。候选风险基因座 在非编码区通常是调控元件，例如增强子和启动子，它们可能调节 决定一种或多种内表型的关键基因的转录活性。对功能的影响 大多数与疾病相关的非编码变异体仍然未知。已知增强剂是细胞型的基础 影响细胞发育和对环境反应的基因表达的特定模式 条件。与遗传风险相关的候选调控序列(CRS)可能是 潜在的内表型并代表潜在的治疗靶点。在过去的十年里，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 仍然无法获得有意义的规章制度要素的功能特征。仅适用于 高通量测序和大规模筛选技术的当代进展，例如 大规模并行报告分析(MPRA)，表征了不断增长的非编码风险基因座列表 集体行动变得可行。我将在HiPSC来源的脑细胞中应用MPRA来识别精神疾病风险变量 在显示细胞类型特异性转录活动的CRS中。此外，我还会在互动中大笑 产前应激和炎症与遗传风险及由此导致的负面心理健康易感性 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有关。 轨迹。怀孕期间的压力或炎症与孕妇的心理健康结局有关 后代。出生前环境因素对脑相关CRSS的影响可以解释与 母体免疫激活(MIA)与儿童对压力和负面健康轨迹的易感性增加 后代。MIA潜在的生物学机制可能有助于这种易感性的增加。使用MPRA， 我将确定大脑相关CRS中的风险变量，这些变量赋予更大的易感性或韧性， 环境应激源。通过评估开发过程中的环境交互作用，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，NIH的资金在全国排名第二。近5,000平方英尺的空间被分配给培训计划 在神经科学系和弗里德曼脑研究所。另外，还有大约100,000英尺2 住房部门和研究所的研究计划和4500平方英尺2专门用于机构核心 设施。这笔奖学金将支持我成为一名多学科、翻译校长的旅程 通过在四个主要领域提供培训，为调查员提供培训：卓越的科学能力。科学联盟。学术性 奖学金。和科学领导力。

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.