Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk
基于增强剂的免疫和 β 细胞失调是 T1D 风险的基础
基本信息
- 批准号:10263319
- 负责人:
- 金额:$ 111.5万
- 依托单位:
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated and
inflammatory cytokines lead to loss of the insulin-producing β cells in the pancreas. Genome-wide association
studies (GWAS) have identified ~60 genomic regions associated with T1D risk. The vast majority of GWAS risk
variants associated with T1D reside in non-coding regions, particularly enhancers, suggesting that gene
regulatory changes substantially contribute to inter-individual differences in susceptibility to T1D. Driven by our
T1D GWAS annotation data, highlighting the importance of a systematic analysis of both immune and β
cell systems of both T1D patients and controls, we propose to identify causal enhancer variants and causal
target genes using contemporary computational methods and cutting-edge global genomics. We will perform our
PRO-cap and PRO-seq assays to comprehensively identify active enhancers harboring T1D-associated variants
in T cells, monocytes and stem cell derived β cells (sc-β cells) from T1D patients and controls, followed by
validation of active enhancers harboring T1D-associated variants using our eSTARR-seq assays (Aim 1). We
will perform our Tri-HiC assays to profile the enhancer-promoter interactomes at unprecedented high resolution
in primary T cells, primary monocytes and sc-β cells from T1D patients and controls as well as pancreatic islets
to comprehensively identify target genes of T1D-associated variants, and refine targets of T1D-associated
variants with T1D-sepcific alteration in target gene expression in each cell type using our coupled single cell
nucleus (sn) RNA-seq and snATAC-seq assays (Aim 2). We will validate targets of T1D-associated variants in
T cells, monocytes and β cells using CRISPR/Cas9 endogenous enhancer mutational strategies in the context
of the endogenous chromatin landscape in each cell type. Our analytical and experimental framework represents
an exciting new paradigm for studying T1D, and the subsequent clinical research based on our results has the
potential to develop preventive and therapeutic strategies against T1D. The data sets generated by these studies
will represent important, but currently lacking, resources for the T1D research community.
抽象的
1型糖尿病(T1D)是一种特定器官特异性的自身免疫性疾病,通过免疫细胞介导并
炎性细胞因子导致胰腺中产生胰岛素的β细胞的损失。全基因组关联
研究(GWAS)已经确定了与T1D风险相关的约60个基因组区域。绝大多数GWAS风险
与T1D相关的变体位于非编码区域,尤其是增强子中,表明基因
监管变化极大地导致了个体间的T1D敏感性差异。由我们的驱动
T1D GWAS注释数据,强调了对免疫和β进行系统分析的重要性
T1D患者和对照组的细胞系统,我们建议鉴定因果增强子变体和因果
使用当代计算方法和尖端的全球基因组学靶向基因。我们将执行我们的
亲帽和pro-seq分析,以全面识别具有T1D相关变体的活跃增强剂
在T细胞中,来自T1D患者和对照的单核细胞和干细胞衍生的β细胞(SC-β细胞),然后是
使用我们的ESTARR-SEQ分析(AIM 1)验证具有T1D相关变体的活性增强剂。我们
将执行我们的Tri-HIC测定法以介绍前所未有的高分辨率的增强子促销相互作用
在原代T细胞中,来自T1D患者和对照组的原代单核细胞和SC-β细胞以及胰岛
全面识别与T1D相关变体的靶基因,并完善与T1D相关的靶标
使用我们的耦合单细胞在每个细胞类型中具有T1D-SEPCIFIC变化的变体
核(SN)RNA-SEQ和SNATAC-SEQ分析(AIM 2)。我们将验证与T1D相关变体的靶标
T细胞,单核细胞和β细胞在情况下使用CRISPR/CAS9内源性增强子突变策略
每种细胞类型中的内源性染色质景观。我们的分析和实验框架代表
一个令人兴奋的新范式用于研究T1D,以及根据我们的结果进行的随后的临床研究具有
针对T1D制定预防和治疗策略的潜力。这些研究产生的数据集
对于T1D研究社区来说,将代表重要但目前缺乏资源。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
Dieter Meinrad Egl...的其他基金
Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk
基于增强剂的免疫和 β 细胞失调是 T1D 风险的基础
- 批准号:1044260510442605
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
DNA repair pathway choice mediates somatic cell reprogramming
DNA修复途径选择介导体细胞重编程
- 批准号:99739449973944
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
DNA repair pathway choice mediates somatic cell reprogramming
DNA修复途径选择介导体细胞重编程
- 批准号:1061890710618907
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk
基于增强剂的免疫和 β 细胞失调是 T1D 风险的基础
- 批准号:1067101210671012
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
DNA repair pathway choice mediates somatic cell reprogramming
DNA修复途径选择介导体细胞重编程
- 批准号:1041322110413221
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
DNA repair pathway choice mediates somatic cell reprogramming
DNA修复途径选择介导体细胞重编程
- 批准号:1024929110249291
- 财政年份:2020
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Novel approaches to map DNA replication traffic in a genome-wide scale
在全基因组范围内绘制 DNA 复制流量图的新方法
- 批准号:99236899923689
- 财政年份:2019
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
相似国自然基金
等位基因聚合网络模型的构建及其在叶片茸毛发育中的应用
- 批准号:32370714
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
基于等位基因非平衡表达的鹅掌楸属生长量杂种优势机理研究
- 批准号:32371910
- 批准年份:2023
- 资助金额:50.00 万元
- 项目类别:面上项目
基于人诱导多能干细胞技术研究突变等位基因特异性敲除治疗1型和2型长QT综合征
- 批准号:82300353
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
ACR11A不同等位基因调控番茄低温胁迫的机理解析
- 批准号:32302535
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
肠杆菌多粘菌素异质性耐药中phoPQ等位基因差异介导不同亚群共存的机制研究
- 批准号:82302575
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Creating an advanced multi-ancestral resource and tools for short tandem repeat analysis in the AOURP researcher workbench
在 AOURP 研究人员工作台中创建先进的多祖先资源和工具,用于短串联重复分析
- 批准号:1079871710798717
- 财政年份:2023
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Itch-specific brain circuit and dopaminergic gene polymorphisms influencing individual differences in itch perception
瘙痒特异性脑回路和多巴胺能基因多态性影响瘙痒感知的个体差异
- 批准号:1073559210735592
- 财政年份:2023
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Genetic and Environmental Influences on Individual Sweet Preference Across Ancestry Groups in the U.S.
遗传和环境对美国不同血统群体个体甜味偏好的影响
- 批准号:1070938110709381
- 财政年份:2023
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Investigating the role of CSF production and circulation in aging and Alzheimer's disease
研究脑脊液产生和循环在衰老和阿尔茨海默病中的作用
- 批准号:1071711110717111
- 财政年份:2023
- 资助金额:$ 111.5万$ 111.5万
- 项目类别:
Injury Response Mediated Pathogenesis in Renal Ciliopathies
损伤反应介导的肾纤毛病发病机制
- 批准号:1057115210571152
- 财政年份:2023
- 资助金额:$ 111.5万$ 111.5万
- 项目类别: