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.

项目摘要 该提案概述了Caleb Lareau博士的五年职业发展计划。为他做准备 为人类基因组学领域的独立研究职业研究，以研究复合物的细胞过程 疾病。候选人将在斯坦福大学进行博士后培训，该大学提供 杰出的环境，以完成拟议的研究并发展大规模计算的技能 分析，基因组技术发展和免疫学。 Lareau博士的导师和顾问，包括 博士。 SatPathy，Kundaje，Greenleaf，Howitt，Curtis和Anderson具有与潜水员有关的技术专业知识 提案的各个方面和指导学员独立的记录的所有方面。此外，候选人将 利用通过斯坦福大学医学院提供的世界一流资源，博士后事务办公室， NHGRI资助的中心在斯坦福大学获得职业发展技能，同时与领导人接触 基因组学。此外，导师实验室中的研究基础设施将使他能够有效地执行 科学目的，在该提案所包含的领域接受培训，并过渡到独立性。 这项工作的目的是开发单细胞基因组学方法来绘制整个躯体进化 人体。最近的大量测序研究的证据表明，体细胞进化发生在 几乎所有组织，但是当前的方法缺乏解决克隆膨胀，相关细胞状态， 或它们在整个身体中的流行。研究躯体进化的关键瓶颈是局限性的 如果解决的话，基因组学技术可能会导致对癌症等疾病的发病机理的见解。 在AIM 1（K99）中，候选人将建立一种新的单细胞方法来衡量可访问的方法 染色质，蛋白质丰度和线粒体DNA突变，以鉴定克隆膨胀和相关细胞 状态变化。在AIM 2（K99）中，候选人将采用多派技术来识别起源和 人类妇科组织和肿瘤中巨噬细胞的扩张。过渡到教师后 AIM 3（R00）的位置，候选人将重点放在创建庞大的单细胞全基因组上 与功能测量配对的测序方法，包括RNA或蛋白质定量。全部 目标将利用并建立在尖端的单细胞多摩学技术上，以研究躯体进化。 对这项研究的追求将导致工具和见解，这些工具和见解将直接告知 人体组织生理学并帮助对年龄相关的早期检测，表征和理解 疾病，包括癌症。生产的所有协议，数据，分析框架和软件工具 在这项研究期间，将免费分发。总的来说，该提案将导致对 分子签名和体细胞进化的调节，并作为博士博士的有效培训计划 拉劳（Lareau）启动了他作为终身调查员的独立职业。