Mapping Integrated Single-Cell Chromatin Accessibility with the Single-Cell Transcriptional Landscape in Pediatric Type 2 Diabetes

绘制儿科 2 型糖尿病中单细胞染色质可及性与单细胞转录景观的整合图谱

• 批准号: 10664557
• 负责人: Lisa Rachel Staimez
• 金额: $ 15.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664557
• 关键词: 21 year old; ATAC-seq; Adult; Advisory Committees; Anti-Inflammatory Agents; Apoptosis; Artificial Intelligence; Automobile Driving; Beta Cell; Bioinformatics; Biological Markers; Blood; Blood specimen; Cell Death; Cells; Cellular Assay; Cessation of life; Childhood; Chromatin; Circulation; Classification; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Complication; Cross-Sectional Studies; DNA Methylation; Data; Data Analyses; Deterioration; Development; Diabetes Mellitus; Diabetic Nephropathy; Discipline; Disease; Distress; Epidemiology; Epigenetic Process; FOXP3 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Grant; Helper-Inducer T-Lymphocyte; Immunophenotyping; Individual; Inflammation; Inflammatory; Infrastructure; Insulin; Insulin Resistance; Investigation; Laboratories; Leadership; Life Cycle Stages; Life Style Modification; Machine Learning; Malignant Neoplasms; Maps; Measurement; Measures; Mentors; Metabolic Diseases; Methods; Methylation; Molecular; Molecular Profiling; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Organ Transplantation; Parents; Participant; Peripheral Nervous System Diseases; Phenotype; Predisposition; Prevention; RNA; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Retinal Diseases; Site; Source; Specificity; Structure of beta Cell of islet; Symptoms; T-Lymphocyte; Techniques; Testing; Time; Tissue-Specific Gene Expression; Training; Translations; Transposase; United States National Institutes of Health; Visit; Youth; aged; aspirate; cell free DNA; cell type; diabetes pathogenesis; disorder control; disorder prevention; epigenetic regulation; epigenomics; experience; gene regulatory network; glycemic control; improved; indexing; innovation; inter-individual variation; islet; multiple omics; novel marker; peripheral blood; pharmacologic; prenatal testing; preservation; prevent; recruit; risk stratification; single cell sequencing; single cell technology; skills; sociodemographics; success; systemic inflammatory response; transcription factor; transcriptome sequencing; transcriptomics; translational applications

ABSTRACT A time-sensitive window of opportunity exists in preventing and treating type 2 diabetes (T2D) in youth where the identification of new molecular targets could be used for disease prevention and control. The key objectives of this proposal are twofold. First, this proposal provides a combined strategy of didactic training and mentored training for (a) the measurement of single-cell chromatin accessibility and single-cell transcription factors associated with T2D using innovative wet-lab techniques; (b) bioinformatics, including machine learning, for the integration of multi-omic, clinical, and sociodemographic data to classify phenotypes of T2D; and (c) leadership and management skills required of high-quality clinical studies. The co-mentors will provide integrated training in single-cell epigenomic and transcriptomic lab techniques, data analyses, and coordinated training with four advisory committee experts. The second key objective of this proposal is the implementation of hypothesis- driven research aims around subtypes of immune cells that have pro-inflammatory vs. anti-inflammatory function. Single-cell sequencing will overcome the limitations of bulk epigenetic and RNA studies and improve attribution of gene regulation in individual cell types. We leverage the recruitment platform from our KL2 parent study to recruit youth and examine single-cell chromatin accessibility associated with T2D. In this cross sectional study, we will collect new peripheral blood samples from two groups of youth aged 10-20-years: new- onset T2D case participants (n=96,000 cells from 24 participants) and healthy, normoglycemia control participants (n=96,000 cells from 24 participants), obtained during a single study visit by oral glucose tolerance test. Our specific aims include (a) testing the hypothesis that T helper (Th)-17 cells will be more abundant in T2D compared to healthy control participants and regulatory T cells (Treg) more abundant in control participants, (b) testing the hypothesis that genes determining T Helper cell type, Rorc and Foxp3, will have different levels of chromatin accessibility and different gene expression in clinical groups, and (c) machine learning based on high-throughput single-cell epigenomic, transcriptomic, sociodemographic, and clinical data to classify phenotypes of T2D. In summary, this proposal assembles a team of mentors and advisors across scientific disciplines to provide thorough training in research related to single-cell epigenetics, gene expression, bioinformatics, machine learning, and leadership in clinical studies, with emphasis on the development of future research for NIH grant support. The innovations of the proposed analyses, namely the integration of single cell epigenetic and single cell gene expression, will enable construction of gene regulatory networks that may inform new strategies to protect youth from T2D and related complications.

抽象的 在预防和治疗2型糖尿病（T2D）的年轻人中，存在时间敏感的机会窗口 新分子靶标的识别可用于预防疾病和控制。关键目标 该提议的两个是双重的。首先，该建议提供了教学培训的综合策略和指导 （a）单细胞染色质可及性和单细胞转录因子的培训 与T2D使用创新的湿与LAB技术相关； （b）生物信息学，包括机器学习，用于 多运动，临床和社会人口统计学数据的整合以对T2D的表型进行分类； （c）领导 以及高质量临床研究所需的管理技能。委托人将提供综合培训 在单细胞表观基因组学和转录组实验室技术中，数据分析和协调的培训与四个 咨询委员会专家。该提案的第二个关键目标是实施假设 - 驱动的研究旨在围绕具有促炎和抗炎的免疫细胞的亚型 功能。单细胞测序将克服大量表观遗传学和RNA研究的局限性，并改善 基因调控单个细胞类型的归因。我们利用KL2父母的招聘平台 研究招募青年并检查与T2D相关的单细胞染色质可及性。在这个十字架中 分区研究，我们将从两组10-20岁的青年中收集新的外周血样本： 发作T2D病例参与者（n =来自24名参与者的96,000个细胞）和健康的正常血糖控制 参与者（来自24名参与者的n = 96,000个细胞），在一次研究访问期间通过口服葡萄糖耐受性获得 测试。我们的具体目的包括（a）测试T辅助器（Th）-17细胞将更丰富的假设 与健康对照参与者和调节性T细胞（TREG）相比，T2D在对照方面更丰富 参与者（b）测试确定T辅助细胞类型的基因RORC和FOXP3的假设， 临床组中不同水平的染色质可及性和不同的基因表达，（c）机器 基于高通量单细胞表观基因组学，转录学，社会人口统计学和临床​​数据的学习 分类T2D的表型。总而言之，该提案组建了一组导师和顾问团队 科学学科，提供有关单细胞表观遗传学，基因表达，彻底培训， 临床研究中的生物信息学，机器学习和领导力，重点是 NIH赠款支持的未来研究。拟议分析的创新，即集成 单细胞表观遗传学和单细胞基因表达，将实现基因调节网络的构建 可能会为保护青年免受T2D和相关并发症的新策略提供信息。