Dissecting dynamic genetic effects from thymus development to immune-mediated disease

项目概述：免疫和炎症活动的不平衡是免疫介导的疾病的标志。 放松。全基因组关联研究已经确定了艾德数百个增加免疫易感性的基因座， 介导的疾病。这些遗传变异的功能性影响很难推断，因为它们可能只影响一个基因。 特定的细胞类型及其影响可能仅限于发育中的特定点。成人免疫研究 细胞揭示了介体细胞和疾病相关变异的机制，然而，童年是一个 这是免疫系统发展的关键阶段，但尚未得到充分研究。T细胞发育的遗传决定因素- 儿童时期的免疫调节和效应功能尚未研究，它们在免疫介导的疾病中的作用 不明 我们建议填补将免疫介导疾病的遗传学与其效应细胞、发育和免疫相关性联系起来的空白。 谈话阶段和机制。我们的目标是：1）了解基因介导的T 细胞发育和免疫介导的疾病的中枢耐受诱导，以及2）鉴定 儿童期免疫表型对成年期疾病的重要性。 为了达到这些目标，我们建议使用基因芯片研究人类T细胞发育的动态遗传影响。 人类儿科胸腺样本中的单细胞基因表达定量性状图谱。研究基因 从发育到外周效应功能的进展，我们将收集外周免疫细胞， 同样的儿科病人。此外，我们还将研究遗传对不同年龄儿童免疫细胞的影响。 激活状态，以确定对刺激起作用的遗传效应。为了研究遗传对免疫系统的影响， 我们将整合我们在儿科免疫细胞中识别的遗传效应， 来自其他研究的成人和新生儿细胞。最后，我们将研究遗传对中枢和外周神经系统的影响。 免疫表型在免疫介导的疾病的情况下。我们将生成染色质接近的特征， 在胸腺和外周免疫细胞中鉴定染色质调节机制的能力。这将使我们能够 进行免疫介导的疾病变异、免疫细胞相关变异和开放性疾病的共定位研究。 染色质区域。然后，我们将估计免疫表型对免疫介导的疾病的因果关系， a孟德尔随机化框架。 总之，我们的研究提供了一种研究复杂疾病机制的创新方法：它结合了 定量遗传学和免疫学使用临床标本产生新的见解的遗传学 免疫介导的疾病，其效应细胞和分子机制。这种机械的理解 疾病相关变异是推进免疫介导疾病新治疗的基础， 放松。

PROJECT SUMMARY: Imbalance of immune and inflammatory activity is a hallmark of immune-mediated dis- eases. Genome-wide association studies have identified hundreds of loci that increase susceptibility to immune- mediated diseases. Functional effects of these genetic variants are difficult to infer as they might only impact a particular cell type and their effects may be restricted to specific points in development. Studies on adult immune cells have shed light on mediator cells and mechanisms of disease-associated variants, however, childhood is a critical yet understudied stage in the development of the immune system. Genetic determinants of T cell develop- ment and effector function during childhood have not been studied and their role in immune-mediated diseases is unknown. We propose to fill gaps that link the genetics of immune-mediated diseases to their effector cells, developmen- tal stages, and mechanisms. Our goals are 1) to understand the importance of genetically mediated T cell development and central tolerance induction on immune-mediated diseases and 2) to identify the importance of childhood immune phenotypes on disease in adulthood. To reach these goals, we propose studying the dynamic genetic influences of human T cell development using single-cell gene expression quantitative trait mapping in human pediatric thymus samples. To study the genetics of the progression from development to peripheral effector function, we will collect peripheral immune cells from the same pediatric patients. Furthermore, we will study genetic effects on pediatric immune cells in different activation states to pinpoint genetic effects acting upon stimulation. To investigate genetic effects on immune cells at different ages, we will integrate the genetic effects we identify in pediatric immune cells with those derived from adult and neonatal cells from other studies. Lastly, we will examine genetic effects on central and peripheral immune phenotypes in the context of immune-mediated diseases. We will generate profiles of chromatin accessi- bility in thymus and peripheral immune cells to identify regulatory mechanisms in chromatin. This will allow us to conduct colocalization studies of immune-mediated disease variants, immune cell-associated variants and open chromatin regions. We will then estimate causality of immune phenotypes on immune-mediated diseases using a Mendelian Randomization framework. In summary, our research offers an innovative approach to study complex disease mechanisms: it combines quantitative genetics and immunology using clinical specimens to generate new insights into the genetics of immune-mediated diseases, their effector cells and molecular mechanisms. This mechanistic understanding of disease-associated variants is fundamental for advancing towards novel treatments of immune-mediated dis- eases.