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: 10653103
• 负责人: Shuibing Chen
• 金额: $ 74.49万
• 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/10653103
• 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; Functional disorder; Genes; Genetic; Genetic Variation; Genetic study; Goals; Homeostasis; Human; Hyperglycemia; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Insulin-Dependent Diabetes Mellitus; Interleukin-1 beta; Islet Cell; Islets of Langerhans; Knowledge; Laboratories; Macrophage; 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; 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; 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 细胞破坏所致。 （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发挥着关键作用。 了解内在和环境网络特征动态将有助于剖析分子 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，系统地探索内在的 在初步研究中，我们进行了单细胞研究。 健康、自身抗体阳性（均为非 高血糖和高血糖）患者胰岛样本，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进行细胞特异性标记。 使用同基因人类多能干细胞（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核苷酸多态性的生物学功能。 在这里，我们将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来 深入研究关键内在和环境信号动力学在 T1D 进展中的作用， 为了实现这些目标，我们建立了控制胰腺β细胞功能障碍的机制网络。 三个具体目标： 目标 1：确定 T1D 进展过程中细胞特异性的内在和环境特征。 目标 2：解码控制 T1D 进展的细胞特异性基因调控网络。 目标 3：使用 T1D 进展验证细胞、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 T1D 胰岛。 我们的主要成果包括：1) 健康、健康的单细胞分辨率多组学（scRNA-seq、scATAC-seq）图谱 T1D 和细胞因子或 CVB4 处理的人类胰岛；2) 细胞/背景特异性分子遗传学 (e/caQTL) 人胰岛中内在信号和环境信号的网络和中心特征；3) 同基因 hPSC- 衍生的 β 细胞和免疫细胞具有 T1D 相关（中心）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准疾病进展标记物奠定基础。

项目成果

A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.

多类器官平台将 CIART 确定为 SARS-CoV-2 感染的关键因素。

• 发表时间: 2023-03
• 影响因子: 21.3
• 作者: Tang, Xuming;Xue, Dongxiang;Zhang, Tuo;Nilsson;Carrau, Lucia;Duan, Xiaohua;Gordillo, Miriam;Tan, Adrian Y;Qiu, Yunping;Xiang, Jenny;Schwartz, Robert E;tenOever, Benjamin R;Evans, Todd;Chen, Shuibing
• 通讯作者: Chen, Shuibing

An integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D associated genes and regulatory signals.

人类胰岛的综合单细胞多组学分析可识别 T1D 相关基因和调节信号。

• 发表时间: 2023-10-18
• 作者: Zhao, Zeping;D'Oliveira Albanus, Ricardo;Taylor, Henry;Tang, Xuming;Han, Yuling;Orchard, Peter;Varshney, Arushi;Zhang, Tuo;Manickam, Nandini;Erdos, Mike;Narisu, Narisu;Taylor, Leland;Saavedra, Xiaxia;Zhong, Aaron;Li, Bo;Zhou, Ting;Naji, Al
• 通讯作者: Naji, Al

Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits.

使用深度学习对胰岛增强子进行建模，识别与 T2D 和血糖特征相关的基因座的候选因果变异。

• 发表时间: 2023-08-29
• 影响因子: 11.1
• 作者: Hudaiberdiev, Sanjarbek;Taylor, D Leland;Song, Wei;Narisu, Narisu;Bhuiyan, Redwan M;Taylor, Henry J;Tang, Xuming;Yan, Tingfen;Swift, Amy J;Bonnycastle, Lori L;Consortium, Diamante;Chen, Shuibing;Stitzel, Michael L;Erdos, Michael R;Ovcharenko
• 通讯作者: Ovcharenko

Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.

检查点激酶 2 控制胰岛素分泌和葡萄糖稳态。

• DOI: 10.1038/s41589-023-01466-4
• 发表时间: 2023-11-09
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: A. Chong;J. V;ana;ana;Ginnie Jeng;Ge Li;Zihe Meng;Xiaohua Duan;Tuo Zhang;Yunping Qiu;Raimon Duran;Kimberly E. Coker;Wei Wang;Yanjing Li;Zaw Min;Xi Zuo;Neranjan de Silva;Zhengming Chen;Ali Naji;Mingming Hao;Chengyang Liu;Shuibing Chen
• 通讯作者: Shuibing Chen

Phenotypic technologies in stem cell biology.

干细胞生物学中的表型技术。

• DOI: 10.1016/j.chembiol.2021.02.001
• 发表时间: 2021-03-18
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Vandana JJ;Lacko LA;Chen S
• 通讯作者: Chen S