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

项目摘要：免疫和fl炎症活动失衡是免疫介导性疾病的标志。 放松点。全基因组关联研究已经确定了成百上千个增加免疫易感性的基因座fi 媒介疾病。这些遗传变异的功能效应很难推断，因为它们可能只影响 特定的细胞类型及其影响可能仅限于发育中的特定fic点。成人免疫的研究进展 细胞已经阐明了疾病相关变异的中介细胞和机制，然而，童年是一种 免疫系统发育的关键但未被充分研究的阶段。T细胞发育的遗传决定因素- 儿童时期的基因和效应器功能尚未被研究，以及它们在免疫介导性疾病中的作用 是未知的。 我们提出了将免疫介导性疾病的遗传学与其效应细胞联系起来的fi11缺口，发展成 TAL阶段和机制。我们的目标是1)了解基因介导的T细胞的重要性 免疫介导性疾病的细胞发育和中枢耐受诱导以及2)鉴定 儿童免疫表型在成年疾病中的重要性。 为了达到这些目标，我们建议用以下方法研究人类T细胞发育的动态遗传fl 儿童胸腺样本中单细胞基因表达的定量性状定位。学习遗传学 在从发育到外周效应功能的过程中，我们将从 同样的儿科病人。此外，我们还将研究不同遗传因素对儿童免疫细胞的影响。 激活状态，以确定作用于刺激的遗传效应。研究遗传对免疫的影响 不同年龄的细胞，我们将把我们在儿科免疫细胞中识别的遗传效应与那些源自 来自其他研究的成人和新生儿细胞。最后，我们将研究基因对中枢和外周的影响 免疫介导性疾病背景下的免疫表型。我们将产生染色质附件的PROfiLE- 在胸腺和外周免疫细胞中识别染色质的调节机制。这将使我们能够 对免疫介导型疾病变异体、免疫细胞相关变异体和开放的变异体进行共定位研究 染色质区域。然后我们将评估免疫表型与免疫介导性疾病的因果关系。 孟德尔随机化框架。 总之，我们的研究为研究复杂的疾病机制提供了一种创新的方法：它结合了 数量遗传学和免疫学使用临床标本产生对遗传病遗传学的新见解 免疫介导性疾病及其效应细胞和分子机制。这种机械性的理解 疾病相关变异是迈向免疫介导性疾病新疗法的基础 放松点。

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.