A New Genetic Tool for Lineage Tracing of Mitotic Cells in Mice

用于小鼠有丝分裂细胞谱系追踪的新遗传工具

• 批准号: 8225585
• 负责人: Yuan Zhuang
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225585
• 关键词: Adult; Aging; Animal Model; Antigens; Apoptosis; Area; Behavior; Biocompatible Materials; Biological Assay; Biomedical Research; Cell Culture Techniques; Cell Maintenance; Cells; Clonal Expansion; Development; Effector Cell; Event; Exposure to; Generations; Generic Drugs; Genetic; Genetic Markers; Genetic Models; Genetic Recombination; Histocompatibility Testing; Homeostasis; Human Genome; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunology; Individual; Label; Life; Listeria monocytogenes; Location; Lymphocyte; Lymphoid; Maintenance; Mediating; Memory; Methods; Mitosis; Mitotic; Mitotic Recombination; Modeling; Mus; NIH Program Announcements; National Center for Research Resources; Outcome; Physiologic pulse; Proliferating; Reporter; Research; S-Phase Fraction; Sister Chromatid; Skin; Solid; Specificity; Stem cells; System; T memory cell; T-Lymphocyte; Techniques; Testing; Tissues; Transgenes; Transgenic Organisms; Vaccination; Viral Tumor Antigens; Work; abstracting; aged; animal model development; base; biological research; cell behavior; daughter cell; design; experience; experimental analysis; gastrointestinal epithelium; in vivo; mouse model; pathogen; pathogen exposure; progenitor; research study; response; stem; tissue regeneration; tool

DESCRIPTION (provided by applicant): A New Genetic Tool for Lineage Tracing of Mitotic Cells in Mice Abstract Mitosis represents one of the most important signatures of somatic stem cells and progenitor cells. The proliferative activity of these cells is essential for supporting tissue functions, replacing damaged or aged tissues, and maintaining tissue homeostasis. Due to the limitations of lineage tracing tools, we still know little about how and to what extent somatic stem or progenitor cells contribute to the function and homeostasis of somatic tissues. The adaptive immune system provides one of the best examples to study the dynamic relationship between the proliferative burst of progenitors and tissue homeostasis. During an immune response to pathogens antigen-specific lymphocytes undergo vigorous clonal expansion. These newly generated effector cells are quickly removed through apoptosis following pathogen clearance. A small fraction of antigen-experienced cells develops into memory cells, which are long lived and are capable of further expansion during subsequent exposure to the same antigen. The generation and homeostatic maintenance of memory lymphocytes are critical for long lasting immunity. Thus far, the origin and fate of memory lymphocytes are still not completely understood. We are developing a unique Cre/lox mediated mitotic recombination system in mice. Using this reporter system, any proliferating cells in adult mice may be pulse labeled with a visible marker for long term tracing of these cells and their descendants. We plan to use this genetic marking system to label and trace memory T cells derived from an immune response to pathogens. We will examine the development, location, and maintenance of memory T cells after primary and secondary pathogen exposure. Because the experimental system is designed to mark the descendants of any dividing cells, the system should also be useful for tracing and analyzing clonal behavior of progenitors or stem cells in tissue types beyond the lymphoid system. We anticipate a broad application of this marking system in the fields such as tissue regeneration, aging, and immunological memory. PUBLIC HEALTH RELEVANCE: The proposed research will provide a new research tool for experimental analysis of immune cells and stem cells in animal models. The outcome will impact our understanding of immune memory and stem cell behaviors.

描述（由申请人提供）：一种用于小鼠有丝分裂细胞谱系追踪的新遗传工具摘要有丝分裂是体干细胞和祖细胞最重要的特征之一。这些细胞的增殖活性对于支持组织功能、替换受损或老化的组织以及维持组织稳态是必不可少的。由于谱系追踪工具的局限性，我们对体干细胞或祖细胞如何以及在多大程度上对体组织的功能和内稳态做出贡献仍然知之甚少。适应性免疫系统为研究祖细胞增殖爆发与组织稳态之间的动态关系提供了最好的范例之一。在对病原体的免疫应答期间，抗原特异性淋巴细胞经历剧烈的克隆扩增。这些新产生的效应细胞在病原体清除后通过凋亡迅速去除。一小部分经历抗原的细胞发育成记忆细胞，其寿命长，并且能够在随后暴露于相同抗原期间进一步扩增。记忆淋巴细胞的产生和稳态维持对于持久的免疫至关重要。到目前为止，记忆淋巴细胞的起源和命运仍不完全清楚。我们正在开发一个独特的Cre/lox介导的有丝分裂重组系统在小鼠中。使用这种报告系统，成年小鼠中的任何增殖细胞都可以用可见标记物进行脉冲标记，用于长期追踪这些细胞及其后代。我们计划使用这种遗传标记系统来标记和追踪来自病原体免疫反应的记忆T细胞。我们将研究原发性和继发性病原体暴露后记忆T细胞的发育、定位和维持。因为实验系统被设计为标记任何分裂细胞的后代，所以该系统也应该可用于追踪和分析淋巴系统以外的组织类型中的祖细胞或干细胞的克隆行为。我们预期这种标记系统在组织再生、衰老和免疫记忆等领域有广泛的应用。 公共卫生关系：这项研究将为动物模型中免疫细胞和干细胞的实验分析提供新的研究工具。结果将影响我们对免疫记忆和干细胞行为的理解。