Multi-omic genetic regulatory signatures underlying tissue complexity of diabetes in the pancreas at single-cell spatial resolution

单细胞空间分辨率下胰腺糖尿病组织复杂性的多组学遗传调控特征

• 批准号: 10684817
• 负责人: Marcela Brissova
• 金额: $ 65.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684817
• 关键词: Acinar Cell; Adult; Age; Alpha Cell; American; Architecture; Beta Cell; Biological; Biology; Cell Differentiation process; Cell Nucleus; Cells; Chromatin; Complex; Computer Analysis; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Dimensions; Disease; Ductal Epithelial Cell; Elements; Endocrine; Enhancers; Environmental Risk Factor; Ethnic Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomic approach; Genomics; Genotype; Glucose; Growth; Heritability; Heterogeneity; Hormone secretion; Human; Image; In Situ; Individual; Inflammation; Insulin; Interdisciplinary Study; Islets of Langerhans; Knowledge; Location; Machine Learning; Macrophage; Maps; Measures; Medical Care Costs; Molecular; Molecular Analysis; Natural regeneration; Neighborhoods; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Pattern; Physiological; Physiology; Play; Prediabetes syndrome; Process; Proteomics; Quantitative Trait Loci; RNA; Regulator Genes; Regulatory Element; Research; Resolution; Resources; Role; Signal Transduction; Single Nucleotide Polymorphism; Specificity; Technology; Text; Tissue imaging; Tissues; Transcriptional Regulation; Translating; Untranslated RNA; Weight; XCL1 gene; cell type; centralized portal; data sharing; diabetes risk; epigenomics; functional genomics; genetic signature; genome wide association study; in situ imaging; insight; islet; multi-ethnic; multimodality; multiple omics; personalized therapeutic; sex; tool; trait; transcriptome; transcriptomics

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Diabetes is a complex disease that results from the cumulative temporal effects of genetic and environmental factors. A hallmark of both common and rare forms of diabetes is genetic dysregulation of insulin-producing β cells which reside in islets of Langerhans and are scattered throughout the larger context of the entire pancreas. Although genome wide association studies (GWAS) of type 2 diabetes (T2D), the most common form of diabetes, identified >600 statistically independent signals, they are difficult to translate into biological mechanisms because of their predominant noncoding location. Therefore, we propose to map the context specificity of T2D and related trait GWAS signals in pancreas across multiple dimensions: cell type, age, sex, developmental stage, and genetic background. Our proposal is based on our exciting single-cell multi-omic spatially-resolved pilot data and the well-supported idea that noncoding GWAS signals percolate upwards through complex and hierarchical molecular networks that influence cellular circuits. The initial layer in this hierarchy is chromatin organization, which propagates genetic predisposition onto subsequent molecular layers, likely starting with the transcriptome. Because islet physiology is influenced by the identity and spatial arrangement of surrounding cells within the pancreas, our multimodal molecular analyses will focus on four major pancreatic lineages; endocrine α and β cells, acinar, and ductal cells. In addition, we will incorporate the analysis of tissue resident macrophages because they play an important role in several processes including islet/pancreatic cell differentiation, growth, regeneration, and inflammation. The proposed studies will establish associations between regulatory elements, genes, cell types, tissue organization, and physiological function. Our multidisciplinary research team with complementary expertise in pancreas and islet biology, sequencing technologies, single cell genomics and epigenomics, image data analysis, and machine learning devised a suite of tools and analyses to discover cell state dynamic changes across diverse conditions, and how these changes influence downstream biology from transcriptional regulation, to cellular spatial organization within the pancreas, and finally to tissue-level physiology. This approach, if successful, will enable mechanistic insights across GWAS loci, which can inform new personalized therapeutic strategies.

在此处输入文本，这是您的应用程序的新摘要信息。此部分不得超过30行文本。 糖尿病是一种复杂的疾病，是遗传和环境因素累积的时间效应的结果。常见和罕见形式的糖尿病的一个标志是胰岛素产生β细胞的遗传失调，这些细胞存在于胰岛中，并分散在整个胰腺的更大范围内。尽管2型糖尿病（T2 D）（最常见的糖尿病形式）的全基因组关联研究（GWAS）确定了>600个统计学独立的信号，但由于其主要的非编码位置，它们难以转化为生物学机制。因此，我们建议在多个维度上绘制胰腺中T2 D和相关性状GWAS信号的背景特异性：细胞类型，年龄，性别，发育阶段和遗传背景。我们的建议是基于我们令人兴奋的单细胞多组学空间分辨的试点数据和良好的支持的想法，即非编码GWAS信号通过影响细胞电路的复杂和分层的分子网络向上渗透。这个层次结构中的第一层是染色质组织，它将遗传易感性传播到随后的分子层，可能从转录组开始。由于胰岛生理学受胰腺内周围细胞的特性和空间排列的影响，我们的多模式分子分析将集中在四个主要的胰腺谱系：内分泌α和β细胞，腺泡和导管细胞。此外，我们将纳入组织驻留巨噬细胞的分析，因为它们在包括胰岛/胰腺细胞分化，生长，再生和炎症在内的几个过程中发挥重要作用。拟议的研究将建立调控元件，基因，细胞类型，组织组织和生理功能之间的关联。我们的多学科研究团队在胰腺和胰岛生物学，测序技术，单细胞基因组学和表观基因组学，图像数据分析和机器学习方面具有互补的专业知识，设计了一套工具和分析，以发现不同条件下的细胞状态动态变化，以及这些变化如何影响下游生物学，从转录调控到胰腺内的细胞空间组织，最后是组织水平的生理学。这种方法，如果成功的话，将使跨GWAS基因座的机制见解，这可以为新的个性化治疗策略提供信息。