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: 10909474
• 负责人: Caleb Andrew Lareau
• 金额: $ 24.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10909474
• 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; Constitutional; Cues; DNA; Data; Development; Disease; Doctor of Philosophy; Early Diagnosis; Endometrial Neoplasms; Environment; Epigenetic Process; Evolution; Faculty; Funding; Future; Generations; Genomic approach; Genomics; Goals; Growth; Gynecologic; Hematopoietic; Human; Human body; Immune; Immune system; Immunology; Innate Immune System; Libraries; Link; Macrophage; 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; Postdoctoral Fellow; 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; Universities; Vertebral column; Work; XCL1 gene; Yolk Sac; analytical tool; assay development; cancer cell; career; career development; cell type; combinatorial; cost; early detection biomarkers; genome sequencing; genome-wide; human genomics; human tissue; improved; indexing; innovation; insight; 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.

项目概要 该提案概述了 Caleb Lareau 博士的五年职业发展计划，为他做好准备。 从事人类基因组学的独立研究生涯，研究复杂的细胞过程 候选人将在斯坦福大学进行博士后培训，该大学提供了 完成拟议的大规模计算研究和开发技能的出色环境 Lareau 博士的导师和顾问，包括分析、基因组技术开发和免疫学。 Satpathy、Kundaje、Greenleaf、Howitt、Curtis 和 Anderson 博士拥有与以下领域相关的多种技术专业知识： 提案的所有方面以及指导受训者独立的记录此外，候选人将。 利用斯坦福大学医学院博士后事务办公室提供的世界一流资源， 和 NHGRI 资助的斯坦福中心，在与领导者交流的同时获得职业发展技能 此外，他的导师实验室内的研究基础设施将使他能够高效地工作。 科学目标，接受本提案所涵盖领域的培训，并过渡到独立。 这项工作的目标是开发单细胞基因组学方法来绘制整个体细胞进化图 最近的批量测序研究的证据表明，体细胞进化发生在 几乎所有组织，但目前的方法缺乏解决克隆扩增、相关细胞状态、 或其在全身的普遍性是研究体细胞进化的一个关键瓶颈。 基因组学技术如果得到解决，可能会深入了解癌症等疾病的发病机制。 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性 染色质、蛋白质丰度和线粒体 DNA 突变，以识别克隆扩增和相关细胞 在目标 2 (K99) 中，候选人将应用多组学技术来识别起源和状态变化。 巨噬细胞在人类妇科组织和肿瘤中的扩张。 目标 3（R00）的职位，候选人将集中精力创建大规模单细胞全基因组 与功能测量（包括 RNA 或蛋白质定量）相结合的测序方法。 目标将利用并建立在尖端的单细胞多组学技术的基础上来研究体细胞进化。 总之，这项研究的追求将产生直接告知属性的工具和见解。 人体组织生理学，有助于早期检测、表征和理解与年龄相关的组织 疾病，包括癌症。产生的所有协议、数据、分析框架和软件工具。 总的来说，该提案将在本研究期间免费分发。 体细胞进化的分子特征和调节，并作为博士的有效培训计划。 拉罗以终身教授的身份开始了他的独立职业生涯。