Three-dimensional conformation changes associated with T cell memory and autoimmunity

与 T 细胞记忆和自身免疫相关的三维构象变化

基本信息

批准号：
10264086
负责人：
Raymond David Hawkins
金额：
$ 63.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264086
关键词：
3-Dimensional ATAC-seq Architecture Autoimmune Autoimmune Diseases Autoimmunity CD4 Positive T Lymphocytes Cells Chromatin Chronic Disease Complex Data Disease Environmental Risk Factor Gene Expression Gene Expression Regulation Genes Genetic Genome Goals Human Immune system Immunologic Memory Immunologics Immunotherapy Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Investigation Maps Memory Microscopy Molecular Conformation Pathogenesis Phenotype Play Population Process Property Regulation Regulator Genes Regulatory Element Regulatory T-Lymphocyte Resolution Rheumatoid Arthritis Role Source Specificity T memory cell T-Lymphocyte Tumor Immunity Untranslated RNA Variant Work autoimmune pathogenesis autoreactivity cell type cohort disorder risk effector T cell immune function immune reconstitution improved innovation insight long term memory member precursor cell progenitor risk variant self-renewal stem stem cells transcriptome sequencing two-dimensional

项目摘要

ABSTRACT Autoimmune diseases are complex diseases arising from both genetic and environmental factors. The pathogenesis of autoimmune diseases like type 1 diabetes (T1D) is not mediated by a single cell type of the immune system. The role of noncoding variants in these diseases are largely understudied, but suggest that changes in three-dimensional chromatin architecture could be altered. Early work largely focused on the role of CD4+T helper 1 (Th1) and T helper 17 (Th17) cells, followed by T regulatory cells (Tregs). More recently, T memory stem cells (Tscm) were identified and their role in autoimmunity is just beginning to be investigated. These cells possess stem-like properties of self-renewal and differentiation. Unlike memory cells (Tmem), these cells are long-lived, providing a source of prolonged immune memory. Because of their stem cell state and ability to provide long-term memory, these cells have important implications for autoimmunity, cancer immunity and immune therapies, and reconstitution of the immune system. In the context of autoimmunity that means these cells also provide a reservoir of autoreactive and inflammatory cells that can continue disrupt immune function and contribute to chronic disease. Our own data indicate that these cells are enriched in T1D donors compared to healthy control subjects, which may be associated with disease risk alleles. The overall goal of this proposal is to identify two- and three-dimensional chromatin architecture changes that distinguish CD4+ Tscm cells from their naïve progenitor and derived cell fates and determine how changes specific T1D contribute to disease pathogenesis by profiling pure populations of cell from healthy control and T1D subjects. We will determine if T1D-associated change are prevalent in other autoimmune diseases by also profiling Tscms from RA donors. We will determine what role noncoding disease-associated variants at cis-regulatory elements (CREs) might play in this process. We proposed to integrate 2D and 3D chromatin architecture across a large cohort to precisely determine target genes and mechanisms of cell- and disease-specific gene regulation. Specifically, we will identify cell-type specific chromatin architecture in pure populations of CD4+ subtypes related to stem cell memory by employing capture HiC to map regulatory loops across three key cell types in a cohort of 50 healthy control subjects. To determine if these regulatory loops are altered in a diseased state, we will identify T1D-specific chromatin architecture to determine the role of Tscm cells in prolonged inflammation and autoreactivity. Lastly, we will identify chromatin architecture changes common in autoimmune Tscm cells by profiling an addition 50 subjects with rheumatoid arthritis. The proposed study will use innovative approaches to conduct large-scale assessment of 2D and 3D genome architecture to determine cell- and disease-specific gene regulatory mechanisms using a well-defined human cohort. The proposed study will advance our understanding of the role of memory stem cells in autoimmunity and the effects of noncoding variants on chromatin architecture in a disease-specific manner.

抽象的自身免疫性疾病是由遗传和环境因素共同引起的复杂疾病。 1 型糖尿病 (T1D) 等自身免疫性疾病的发病机制并非由单一细胞类型介导非编码变异在这些疾病中的作用尚未得到充分研究，但表明三维染色质结构的变化可能会改变。早期的工作主要集中在染色质的作用上。 CD4+T 辅助细胞 1 (Th1) 和 T 辅助细胞 17 (Th17) 细胞，其次是 T 调节细胞 (Treg)。记忆干细胞（Tscm）已被鉴定，并且它们在自身免疫中的作用刚刚开始被研究。与记忆细胞（Tmem）不同，这些细胞具有类似干细胞的特性。由于它们的干细胞状态，这些细胞寿命很长，为延长免疫记忆提供了来源。以及提供长期记忆的能力，这些细胞对自身免疫、癌症具有重要意义免疫和免疫治疗，以及在自身免疫的背景下重建免疫系统。意味着这些细胞还提供了可以继续破坏的自身反应性和炎症细胞的储存库我们自己的数据表明，这些细胞在 T1D 中含量丰富。捐赠者与健康对照受试者相比，这可能与疾病风险等位基因有关。该提案的目标是确定区分染色质的二维和三维染色质结构变化来自其幼稚祖细胞和衍生细胞命运的 CD4+ Tscm 细胞，并确定如何改变特定的 T1D 通过分析来自健康对照和 T1D 受试者的纯细胞群，有助于疾病发病机制。我们还将通过分析来确定 T1D 相关变化是否在其他自身免疫性疾病中普遍存在我们将确定来自 RA 供体的非编码疾病相关变异在顺式调节中的作用。我们建议整合 2D 和 3D 染色质架构。跨越一个大队列来精确确定细胞和疾病特异性基因的靶基因和机制具体来说，我们将鉴定纯 CD4+ 群体中的细胞类型特异性染色质结构。通过使用捕获 HiC 来绘制三个关键细胞的调节环路，从而确定与干细胞记忆相关的亚型确定这些调节环路是否在 50 名健康对照受试者中发生改变。在疾病状态下，我们将鉴定 T1D 特异性染色质结构，以确定 Tscm 细胞在最后，我们将确定常见的染色质结构变化。拟议的研究将通过对另外 50 名类风湿性关节炎受试者进行分析来对自身免疫 Tscm 细胞进行分析。使用创新方法对 2D 和 3D 基因组架构进行大规模评估，以确定使用明确的人类队列研究细胞和疾病特异性基因调控机制。研究将增进我们对记忆干细胞在自身免疫中的作用以及记忆干细胞的影响的理解以疾病特异性方式对染色质结构进行非编码变异。