Determining the Intrinsic and Environmental Signal Contributing to Early T1D Progression

确定导致早期 T1D 进展的内在信号和环境信号

• 批准号: 10157473
• 负责人: Shuibing Chen
• 金额: $ 78.78万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10157473
• 关键词: Anti-Inflammatory Agents; Autoantibodies; Autoimmune Responses; Beta Cell; Biological; Biological Process; Biology; Biopsy; Cell Death; Cell Survival; Cells; Cellular biology; Cessation of life; Chromatin; Development; Diabetes Mellitus; Disease; Disease Progression; Environment; Exposure to; Foundations; Functional disorder; Genes; Genetic; Genetic Variation; Genetic study; Goals; Homeostasis; Human; Hyperglycemia; Immune; Individual; Inflammation; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interleukin-1 beta; Islet Cell; Islets of Langerhans; Knowledge; Laboratories; Maps; Modeling; Molecular; Molecular Genetics; Multiomic Data; Mutation; Pancreas; Pathway Analysis; Patients; Play; Population; Population Decreases; Reactive Oxygen Species; Regulatory Element; Resolution; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Structure of beta Cell of islet; TNF gene; Tissues; Validation; Virus; adaptive immune response; base; cell type; cytokine; drug development; endocrine pancreas development; environmental change; experimental study; functional genomics; genetic variant; genome wide association study; human pluripotent stem cell; insulitis; islet; knockout gene; macrophage; multiple omics; network models; novel therapeutics; pathogen; precision medicine; progression marker; response; single-cell RNA sequencing; stem cell biology; stem cell model; trait; transcriptome

Abstract. Type 1 diabetes (T1D) is caused by autoimmune response induced pancreatic β cell destruction. Both intrinsic (beta cell) and environmental (immune cell) signals play critical roles in pancreatic β cell dysfunction and death. Understanding the intrinsic and environmental network signature dynamics will facilitate dissecting the molecular mechanisms controlling T1D progression. Here, we build an interdisciplinary team with the expertise of diabetes computational and functional genomics, stem cell biology, and islet biology to systematically explore the intrinsic and environmental changes during T1D progression. In the preliminary studies, we performed single cell transcriptome (scRNA-seq) and chromatin (scATAC-seq) profiling of healthy, autoantibody positive (both non- hyperglycemia and hyperglycemia) patient islet samples, as well as a laboratory model that mimics T1D islet cell-specific signatures using human islets exposed to either cytokines or virus. In addition, we have created a platform to use isogenic human pluripotent stem cells (hPSCs)-derived pancreatic beta cells and macrophage- like cells to explore the biological function of diabetes associated genes or single nucleotide polymorphisms. Here, we will combine our expertise of diabetes computational and functional genomics and stem cell biology to systematically investigate the role of key intrinsic and environmental signal dynamics in T1D progression and establish the mechanistic network controlling pancreatic beta cell dysfunction. To achieve these goals, we propose three specific aims: Aim 1: Determine the cell-specific intrinsic and environmental signatures during T1D progression. Aim 2: Decode the cell-specific genetic regulatory network controlling T1D progression. Aim 3: Validate cells, genes, genetic variants, and intrinsic and environment signatures in T1D progression using an isogenic hPSC-based platform and primary T1D islets. Our key deliverables include: 1) a single-cell resolution multi-omic (scRNA-seq, scATAC-seq) map of healthy, T1D and cytokine- or CVB4 treated human islets; 2) the cell/context-specific molecular genetic (e/caQTL) network and hub signature of intrinsic and environmental signals in human pancreatic islets; 3) Isogenic hPSC- derived beta and immune cells with T1D-associated (hub) gene knockouts to validate individual or multiple genes. These results will be foundational for development of novel drugs and precision disease progression markers.

抽象的。 1型糖尿病（T1D）是由自身免疫反应引起的胰腺β细胞破坏引起的。两者都有内在 （β细胞）和环境（免疫细胞）信号在胰腺β细胞功能障碍和死亡中起关键作用。 了解内在和环境网络签名动力学将有助于解剖分子 控制T1D进展的机制。在这里，我们建立了一个具有糖尿病专业知识的跨学科团队 计算和功能基因组学，干细胞生物学和胰岛生物学，以系统地探索本质 T1D进展过程中的环境变化。在初步研究中，我们进行了单细胞 健康，自身抗体阳性的转录组（SCRNA-SEQ）和染色质（SCATAC-SEQ）分析（均非 - 高血糖和高血糖）患者胰岛样品，以及模拟T1D胰岛的实验室模型 使用暴露于细胞因子或病毒的人类胰岛的细胞特异性特异性特征。此外，我们创建了一个 使用同源性人多能干细胞（HPSC）衍生的胰腺β细胞和巨噬细胞的平台 像细胞一样探索糖尿病相关基因或单个核苷酸多态性的生物学功能。 在这里，我们将结合糖尿病的专业知识计算和功能基因组学和干细胞生物学 系统地研究关键固有和环境信号动力学在T1D进程中的作用 建立控制胰腺β细胞功能障碍的机械网络。为了实现这些目标，我们 提案三个具体目标： AIM 1：确定T1D进展过程中细胞特异性的内在和环境特征。 AIM 2：解码控制T1D进展的细胞特异性遗传调节网络。 AIM 3：使用T1D进展中的细胞，基因，遗传变异以及内在和环境特征 基于ISEOGION HPSC的平台和主要T1D小岛。 我们的关键可交付成果包括：1）健康的单细胞分辨率多摩变（scrna-seq，scatac-seq）的健康图， T1D和细胞因子或CVB4处理的人类胰岛； 2）细胞/上下文特异性分子遗传（E/CAQTL） 人类胰岛中固有和环境信号的网络和集线器签名； 3）等源性hpsc- 带有T1D相关（HUB）基因敲除的衍生β和免疫细胞，以验证个体或多个基因。 这些结果将是开发新药物和精确疾病进展标志物的基础。