Core A: Single Cell Profiling and Bioinformatics Core

项目总结/摘要 单细胞测序和生物信息学核心（核心A）旨在支持所有计划项目， 他们研究了外部的、可改变的风险因素如何影响克隆性造血的进展， 小鼠和人类血液恶性肿瘤。该计划的两大主题-了解细胞如何与 特定的突变对可改变的压力源作出反应，并评估单个突变克隆对 生态系统中的其他生物-都依赖于细胞的单细胞分析。这个核心的使命是 先进的技术和分析平台，以跟踪和表征人类和小鼠突变细胞， 细胞分辨率，然后是解释数据所需的生物信息学和数学分析。核心 将（1）提供高通量单细胞基因组分析和其他先进的测序平台， 项目;（2）将提供多维数据集的生物信息学分析，并促进数据共享;以及（3） 将根据小鼠和人类的大规模分子数据开发数学模型。支持 第一个目标是，核心配备了各种单细胞基因组学平台，如Chromium（10 X Genomics） 和Tapestri（使命生物），这使得高通量单细胞RNA和DNA测序，以及 单细胞多组学方法（CITE-seq和同时DNA/蛋白质分析）。高桥浩一博士， 核心的领导者，一直站在使用这些技术评估 血液恶性肿瘤，使他非常适合导致这个程序特定的核心。第二个目标， 该核心将为分析大规模表观遗传和转录组数据提供必要的生物信息学支持 对可改变的外在风险因素（项目1中的感染和肥胖; 项目2）了解应激对克隆造血和恶性转化的生物学效应。 在第三个目标中，核心将利用广泛的流行病学数据开发一个数学模型来预测 根据其遗传变异、克隆、 大小（通过变异等位基因频率测量）和特定暴露于可改变的外部风险因素（例如， 吸烟、肥胖、感染、化疗）。Marek Kimmel博士，核心的共同领导人，有一个广泛的 在干细胞动力学和癌症的数学建模的背景，并处于领先地位，这方面 的核心。该核心将协调数据存储和质量控制（QC），以确保 数据的可重复性，并促进公共数据共享。总体而言，核心A将提供尖端技术， 为所有三个拟议项目提供分析支持，并支持统计的严谨性和可重复性， 从核心B。通过集中数据分析和存储，该核心将促进数据集的整合， 横截面分析，以优化大型机械动物和人类之间的串扰 流行病学研究在这个项目中。该核心的工作是该计划阐明以下总体目标的核心： 克隆动态对可改变的外部胁迫的反应机制。

Project Summary/Abstract The Single Cell Sequencing and Bioinformatics Core (Core A) is designed to support all Program Projects in their studies of how external, modifiable risk factors influence the progression of clonal hematopoiesis to hematologic malignancy in mice and humans. Two major themes of the Program – understanding how cells with specific mutations respond to modifiable stressors and evaluating the impact of individual mutant clones on others in the ecosystem – both depend on single-cell analysis of cells. The mission of this Core is to provide advanced technical and analytical platforms to track and characterize human and murine mutant cells at single- cell resolution, followed by bioinformatics and mathematical analyses necessary to interpret the data. The Core will (1) provide high-throughput single-cell genomic analysis and other advanced sequencing platforms to all Projects; (2) will provide bioinformatics analysis of multi-dimensional datasets and facilitate data sharing; and (3) will develop mathematical modeling based on large-scale molecular data from mice and humans. To support the first aim, the core is equipped with various single-cell genomics platforms such as Chromium (10X Genomics) and Tapestri (Mission Bio), which enable high-throughput single-cell RNA and DNA sequencing, as well as single-cell multi-omics approaches (CITE-seq and simultaneous DNA/protein analysis). Dr. Koichi Takahashi, Leader of the Core, has been on the forefront of use of such technologies in evaluating the evolution of hematologic malignancies, making him ideally suited to lead to this Program-specific Core. In the second aim, the Core will provide necessary bioinformatic support in analyzing large-scale epigenetic and transcriptomic data in response to modifiable extrinsic risk factors (infection and obesity in Project 1; chemotherapy and smoking in Project 2) to understand the biological effects of stress on clonal hematopoiesis and malignant transformation. In the third aim, the Core will utilize broad epidemiologic data to develop a mathematical model to predict the risk that CH progresses to frank hematologic malignancy in individuals based on their genetic variants, clone size (as measured by variant allele frequency), and specific exposures to modifiable external risk factors (e.g. smoking, obesity, infection, chemotherapies). Dr. Marek Kimmel, Co-Leader of the Core, has an extensive background in mathematical modeling of stem cell dynamics and cancer and is well-positioned to lead this aspect of the Core. This Core will coordinate data storage and quality controls (QC) to ensure the rigor and reproducibility of the data and facilitate public data sharing. Overall, Core A will provide cutting-edge technical and analytical support for all three proposed Projects and support statistical rigor and reproducibility, with support from Core B. By centralizing data analysis and storage, this Core will facilitate the integration of datasets and cross-sectional analyses in order to optimize crosstalk between the large-scale mechanistic animal and human epidemiology studies in this Program. The work of this Core is central to the Program’s overall goal of elucidating the mechanisms of clonal dynamics in response to modifiable external stressors.