Tracing Cell Lineages

追踪细胞谱系

• 批准号: 9336850
• 负责人: MICHAEL T MCMANUS
• 金额: $ 58.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336850
• 关键词: Adult; Alpha Cell; Animals; Apoptosis; Autoimmunity; Back; Biology; Cell Cycle; Cell Lineage; Cells; Custom; DNA; DNA Binding; Dancing; Development; Developmental Process; Disease; Enzymes; Future Generations; Gene Expression; Genes; Goals; Human; Human body; Individual; Life; Malignant Neoplasms; Metastatic to; Molecular; Monitor; Mus; Music; Neoplasm Metastasis; Organism; Pharmaceutical Preparations; Population; Process; Proteins; RNA; Reagent; Recording of previous events; Records; Reporting; Research Personnel; System; Technology; Time; Tissues; Tracer; Transgenic Mice; Vision; Whole Organism; Writing; cell type; deep sequencing; digital; fascinate; fluidity; innovation; innovative technologies; insight; mouse model; new technology; next generation; novel; novel strategies; plant fungi; programs; public health relevance; reconstruction; stem cell population; tool; zygote

DESCRIPTION (provided by applicant): The adult human body is composed of trillions of cells that all originated from a single fertilized egg cell. In the adult, most tissues are in a state of constant flux, where old cells die and new cells are created from resident populations of stem cells, changing their identities in mysterious ways. The fluidity of change among cell populations initiate from the moment we are conceived- to our final breath of life. Multicellular life dances t the music of a highly ordered process, directed by a score that is not well understood. Disease such as cancer emerges when cells lose their directions, and divide in an uncontrolled manner, losing their identities. Other diseases are hallmarked by a loss of cells, triggered by unwanted self-elimination such as apoptosis or autoimmunity. One of the greatest struggles in biology is to understand these fundamental processes, at the cellular and molecular level. Our idea is to develop a new tool that will help us track the ancestry of individual cells, using a novel DNA barcoding technology. This proposal describes a new approach for tracking the evolutionary history of individual cells- at the most possible granular level, the individual cells. We take advantage of new technologies (deep sequencing and programmable DNA binding enzymes), combining them in a way to create a single cell lineage tracer in which each cell writes its own unique barcode. This system is comprised of a molecular 'typewriter' that types a unique barcode every time a cell goes into cell cycle. Moreover, this written barcode accumulates with each future generation. Our vision is to introduce this system into fertlized zygotes, were mouse lines will be developed. In essence every cell in the mouse will contain a unique barcode, and each barcode would contain information on its ancestral lineage, tracing back to the initial fertilized zygote. We believe that developing a quantitative approach for defining single cell inheritance lineages will transform how the next generation of developmental and disease biologists approach their problems.

描述（由申请人提供）：成年人体由数万亿个细胞组成，这些细胞都来自单个受精卵细胞。在成年人中，大多数组织处于 恒定的流动，旧细胞死亡，新细胞从干细胞的常驻群体中产生，以神秘的方式改变它们的身份。细胞群体之间的变化流动性从我们被孕育的那一刻开始-到我们生命的最后一次呼吸。多细胞生命在一个高度有序的过程的音乐中跳舞，由一个不太清楚的乐谱指挥。当细胞失去方向，以不受控制的方式分裂，失去身份时，就会出现癌症等疾病。其他疾病的特点是细胞损失，由不必要的自我消除（如细胞凋亡或自身免疫）引发。生物学中最大的挑战之一就是在细胞和分子水平上理解这些基本过程。我们的想法是开发一种新的工具，利用一种新的DNA条形码技术，帮助我们追踪单个细胞的祖先。该提案描述了一种跟踪单个细胞进化历史的新方法-在最可能的颗粒水平上，单个细胞。我们利用新技术（深度测序和可编程DNA结合酶），将它们结合在一起，创建一个单细胞谱系示踪剂，其中每个细胞都写有自己独特的条形码。这个系统由一个分子“打字机”组成，每当细胞进入细胞周期时，它就会打出一个独特的条形码。此外，这种书写的条形码随着每一代的后代而积累。我们的设想是将这一系统引入受精卵中，从而开发小鼠品系。从本质上讲，小鼠的每个细胞都包含一个独特的条形码，每个条形码都包含其祖先谱系的信息，可以追溯到最初的受精卵。我们相信，开发一种定量方法来定义单细胞遗传谱系将改变下一代发育和疾病生物学家解决问题的方式。