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.

项目总结

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