Charting somatic evolution via single-cell multiomics

通过单细胞多组学绘制体细胞进化图

• 批准号: 10506162
• 负责人: Caleb Andrew Lareau
• 金额: $ 11.87万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2023-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506162
• 关键词: ATAC-seq; Address; Adult; Age; Antigens; Area; Bioinformatics; Biological; Biological Assay; Cancerous; Cell Differentiation process; Cell Ontogeny; Cell physiology; Cells; Chromatin; Clonal Evolution; Clonal Expansion; Clonality; Complex; Computer Analysis; Constitution; Cues; DNA; Data; Data Analytics; Development; Disease; Doctor of Philosophy; Early Diagnosis; Endometrial Neoplasms; Environment; Epigenetic Process; Evolution; Faculty; Foundations; Funding; Future; Generations; Genomic approach; Genomics; Goals; Growth; Hematopoietic; Human; Human body; Immune; Immune system; Immunology; Innate Immune System; Lead; Libraries; Link; Malignant Neoplasms; Measurement; Measures; Membrane Proteins; Mentors; Methodology; Methods; Mitochondrial DNA; Modality; Molecular; Molecular Profiling; Multiomic Data; Mutation; National Human Genome Research Institute; Nuclear; Pathogenesis; Pathology; Phase; Phenotype; Physiology; Play; Ploidies; Population; Positioning Attribute; Predisposition; Preparation; Prevalence; Process; Program Development; Property; Proteins; Protocols documentation; RNA; Reaction; Records; Regulation; Research; Research Design; Research Infrastructure; Research Personnel; Resolution; Resources; Role; Software Tools; Somatic Mutation; Specific qualifier value; Technical Expertise; Technology; Therapeutic Intervention; Time; Tissues; Training; Training Programs; Transposase; Tumor Tissue; Universities; Vertebral column; Work; XCL1 gene; Yolk Sac; analytical tool; assay development; cancer cell; career; career development; cell type; chromatin protein; combinatorial; cost; early detection biomarkers; genome sequencing; genome-wide; human genomics; human tissue; improved; indexing; innovation; insight; macrophage; medical schools; method development; mitochondrial DNA mutation; multimodality; multiple omics; new technology; novel; ovarian neoplasm; patient stratification; post-doctoral training; premalignant; response; single cell sequencing; single-cell RNA sequencing; skill acquisition; skills; technology development; tenure track; tool; transcriptome; tumor; whole genome

PROJECT SUMMARY This proposal outlines a five-year career development program for Caleb Lareau, Ph.D. to prepare him for an independent research career in human genomics to study cellular processes underlying complex disease. The candidate will conduct his postdoctoral training at Stanford University, which provides an outstanding environment to complete the proposed research and develop skills in massive-scale computational analyses, genomics technology development, and immunology. Dr. Lareau’s mentors and advisors, including Drs. Satpathy, Kundaje, Greenleaf, Howitt, Curtis, and Anderson, have diverse technical expertise relevant to all aspects of the proposal and track records of guiding trainees to independence. Further, the candidate will utilize world-class resources available through the Stanford School of Medicine, Office of Postdoctoral Affairs, and NHGRI-funded Centers at Stanford to acquire career development skills while interfacing with leaders in genomics. Additionally, the research infrastructure within his mentors’ labs will enable him to efficiently perform the scientific aims, receive training in areas encompassed by this proposal, and transition to independence. The goal of this work is to develop single-cell genomics methods to chart somatic evolution throughout the human body. Evidence from recent bulk sequencing studies has indicated that somatic evolution occurs in almost all tissues, but current approaches lack sensitivity to resolve clonal expansions, associated cell states, or their prevalence throughout the body. A key bottleneck in studying somatic evolution has been limitations of genomics technologies, which if addressed, may lead to insights into the pathogenesis of diseases like cancer. In Aim 1 (K99), the candidate will establish a new single-cell approach for measuring accessible chromatin, protein abundance, and mitochondrial DNA mutations to identify clonal expansions and related cell state changes. In Aim 2 (K99), the candidate will apply multi-omics technologies to identify the origins and expansions of macrophages within human gynecological tissues and tumors. After transitioning to a faculty position for Aim 3 (R00), the candidate will focus his effort on creating massive-scale single-cell whole-genome sequencing methods that are paired with functional measurements, including RNA or protein quantification. All Aims will utilize and build upon cutting-edge single-cell multi-omics technologies to study somatic evolution. Together, the pursuit of this research will result in tools and insights that will directly inform properties of human tissue physiology and aid in the early detection, characterization, and understanding of age-associated diseases, including cancer. All protocols, data, analytical frameworks, and software tools that are produced during the duration of this research will be freely distributed. In total, the proposal will lead to novel insights into the molecular signatures and regulation of somatic evolution and serve as an effective training program for Dr. Lareau to launch his independent career as a tenure-track investigator.

项目摘要 该提案概述了Caleb Lareau博士的五年职业发展计划。作准备的 在人类基因组学的独立研究生涯，研究复杂的细胞过程， 疾病候选人将在斯坦福大学进行博士后培训，该大学提供 出色的环境，以完成拟议的研究和发展技能，在大规模的计算 分析、基因组学技术开发和免疫学。Lareau博士的导师和顾问，包括 Drs. Satpathy、Kundaje、Greenleaf、Howitt、Curtis和安德森拥有与以下方面相关的各种技术专长： 各方面的建议和指导学员独立的记录。此外，候选人将 利用斯坦福大学医学院，博士后事务办公室， 和NHGRI资助的斯坦福大学中心，以获得职业发展技能，同时与领导人在 基因组学此外，他导师实验室内的研究基础设施将使他能够有效地执行 科学目标，接受本提案所涵盖领域的培训，并过渡到独立。 这项工作的目标是发展单细胞基因组学方法，以图表体细胞进化的整个 人体的最近大量测序研究的证据表明，体细胞进化发生在 几乎所有的组织，但目前的方法缺乏分辨克隆扩增，相关细胞状态， 或者它们在全身的普遍性。研究体细胞进化的一个关键瓶颈是 基因组学技术，如果得到解决，可能会导致对癌症等疾病的发病机制的见解。 在目标1（K99）中，候选人将建立一种新的单细胞方法来测量可访问的 染色质，蛋白质丰度和线粒体DNA突变，以确定克隆扩增和相关细胞 状态变化。在目标2（K99）中，候选人将应用多组学技术来识别起源， 人妇科组织和肿瘤内巨噬细胞的扩增。在过渡到一个教师 目标3（R00）的位置，候选人将集中精力创造大规模的单细胞全基因组 与功能测量配对的测序方法，包括RNA或蛋白质定量。所有 Aims将利用并建立在尖端的单细胞多组学技术基础上来研究体细胞进化。 总之，对这项研究的追求将产生工具和见解，这些工具和见解将直接告知 人体组织生理学，并有助于早期检测，表征和理解与年龄相关的 疾病，包括癌症。生成的所有方案、数据、分析框架和软件工具 在本研究期间，将免费分发。总的来说，该提案将导致对以下方面的新见解： 的分子特征和调控的体细胞进化，并作为一个有效的培训计划博士。 Lareau开始了他作为终身制调查员的独立职业生涯。

项目成果

SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9.

• DOI: 10.1016/j.cell.2023.09.002
• 发表时间: 2023-10-26
• 期刊: CELL
• 影响因子: 64.5
• 作者: Schmidt, Nora;Ganskih, Sabina;Wei, Yuanjie;Gabel, Alexander;Zielinski, Sebastian;Keshishian, Hasmik;Lareau, Caleb A.;Zimmermann, Liv;Makroczyova, Jana;Pearce, Cadence;Krey, Karsten;Hennig, Thomas;Stegmaier, Sebastian;Moyon, Lambert;Horlacher, Marc;Werner, Simone;Aydin, Jens;Olguin-Nava, Marco;Potabattula, Ramya;Kibe, Anuja;Doelken, Lars;Smyth, Redmond P.;Caliskan, Neva;Marsico, Annalisa;Krempl, Christine;Bodem, Jochen;Pichlmair, Andreas;Carr, Steven A.;Chlanda, Petr;Erhard, Florian;Munschauer, Mathias
• 通讯作者: Munschauer, Mathias

Subtle cell states resolved in single-cell data.

单细胞数据中解析了微妙的细胞状态。

• DOI: 10.1038/s41587-023-01797-6
• 发表时间: 2023
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: Lareau,Caleb