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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

基本信息

批准号：
10440517
负责人：
Shuibing Chen
金额：
$ 75.32万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
https://reporter.nih.gov/project-details/10440517
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

项目摘要

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。 1型糖尿病（T1 D）是由自身免疫反应诱导的胰腺β细胞破坏引起的。内因性 (beta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。理解内在和环境网络签名动力学将有助于剖析分子生物学。控制T1 D进展的机制。在这里，我们建立了一支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，系统地探索内在的 T1 D进展期间的环境变化。在初步研究中，我们进行了单细胞转录组（scRNA-seq）和染色质（scATAC-seq）分析健康，自身抗体阳性（均为非高血糖症和高血糖症）患者胰岛样品，以及模拟T1 D胰岛的实验室模型使用暴露于细胞因子或病毒的人胰岛的细胞特异性特征。此外，我们还创建了一个平台使用同基因人多能干细胞（hPSC）衍生的胰腺β细胞和巨噬细胞，如细胞，以探索糖尿病相关基因或单核苷酸多态性的生物学功能。在这里，我们将联合收割机结合我们在糖尿病计算和功能基因组学以及干细胞生物学方面的专业知识，系统地研究关键的内在和环境信号动态在T1 D进展中的作用，建立控制胰岛β细胞功能障碍的机制网络。为了实现这些目标，我们提出三个具体目标：目的1：确定T1 D进展期间细胞特异性内在和环境特征。目的2：解码控制T1 D进展的细胞特异性遗传调控网络。目的3：使用T1 D进展中的细胞、基因、遗传变异以及内在和环境特征，基于同基因hPSC的平台和原代T1 D胰岛。我们的主要成果包括：1）健康的单细胞分辨率多组学（scRNA-seq，scATAC-seq）图谱， T1 D和细胞因子或CVB 4处理的人胰岛; 2）细胞/环境特异性分子遗传（e/caQTL）人胰岛中内在和环境信号的网络和中枢特征; 3）同基因hPSC- 衍生的β和免疫细胞与T1 D相关的（枢纽）基因敲除，以验证单个或多个基因。这些结果将为开发新药和精确的疾病进展标志物奠定基础。