Transcriptional regulation of immunological memory in innate and adaptive lymphocytes

先天性和适应性淋巴细胞免疫记忆的转录调节

• 批准号: 10704003
• 负责人: Colleen M. Lau
• 金额: $ 10.8万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704003
• 关键词: Ablation; Antigens; Award; Bioinformatics; CD8-Positive T-Lymphocytes; Cell Therapy; Cells; Cellular immunotherapy; Chromatin; Classification; Clinical; Cre lox recombination system; Cytokine Receptors; Cytokine Signaling; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Data Set; Disease; Epigenetic Process; Exercise; Exhibits; Faculty; Fostering; Gene Deletion; Generations; Genetic; Genetic Transcription; Genome; Genomics; Grant; Growth; High-Throughput Nucleotide Sequencing; Human; Immune; Immunologic Memory; Immunology; Infection; Inflammatory; Institution; Intervention; JUNB gene; Knowledge; Longevity; Lymphocyte; Maintenance; Memory; Mentors; Messenger RNA; Methods; Modeling; Molecular; Murid herpesvirus 1; Mus; Natural Killer Cells; Play; Positioning Attribute; Prevention; Process; Regulation; Research; Research Personnel; Role; T memory cell; T-bet protein; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Transcription Factor AP-1; Transcriptional Regulation; Up-Regulation; Vaccination; Vaccine Therapy; Viral; Virus Diseases; Work; Writing; arm; career; cell type; complex data; cytokine; cytotoxicity; epigenetic memory; epigenomics; human disease; improved; laboratory experiment; mouse model; next generation sequencing; novel; pathogen; posttranscriptional; programs; recruit; response; skills; symposium; tenure track; transcription factor; transcriptome sequencing; transcriptomics; tumorigenesis; vaccine development

PROJECT SUMMARY The candidate, Dr. Colleen Lau seeks to achieve an academic career as an independent research investigator at an institution where she can foster academic growth and immunology research that advances treatment or prevention of human disease. She aims to do so through a union of laboratory experimentation and bioinformatics methods, as reflected in her current proposal. Her project aims to understand the underlying mechanisms that drive proper formation of immune memory by studying it in two cytolytic lymphocytes in the context of viral infection, using mouse cytomegalovirus (CMV) as a model. By studying the infection in mice, work performed previously in the lab has demonstrated that natural killer (NK) cells, cytolytic lymphocytes traditionally classified as innate cells, are capable of exhibiting attributes of adaptive immune memory. As a result, her previous work used these CMV- specific NK cells and the more classic adaptive CD8+ T cell to further illustrate that these two lymphocytes share a common transcriptional and epigenetic memory signature. Building from this signature, she will hone in on two candidate transcription factors, ZEB2 and JunB, to test their requirement for optimal effector function, memory formation, memory maintenance and recall in both cell types, using genetic mouse models that temporally delete the gene. Using a combination of high-throughput sequencing technologies, she will generate global transcriptomic, epigenomic, and transcription factor occupancy profiles in order to elucidate any common mechanisms between memory NK and CD8+ T cells. This proposal improves our understanding of antiviral processes and immune memory in order to ultimately harness it for vaccine therapy and disease intervention. Throughout the transition and award period, the candidate will focus on advancing her technical and computational skills for generating and analyzing large and complex datasets, improving and exercising her mentoring skills, broadening her scientific background through regular attendance of scientific seminars and conferences, and developing her grant writing skills. She aspires to acquire a tenure-track faculty position, and, with the informal guidance of her previous mentors, strives to carry out her long-term research program of studying immunological memory.

项目摘要 候选人Colleen Lau博士寻求作为一项独立研究的学术生涯 她可以促进进步的学术增长和免疫学研究的机构的调查员 治疗或预防人类疾病。她的目标是通过实验室实验结合 和生物信息学方法，如她当前的提议所反映的。 她的项目旨在了解推动免疫形成适当形成的基本机制 使用小鼠在病毒感染的背景下在两个细胞溶解淋巴细胞中研究记忆。 巨细胞病毒（CMV）作为模型。通过研究小鼠的感染，以前在实验室中进行的工作已有 证明自然杀手（NK）细胞，传统上归类为先天细胞的细胞溶解淋巴细胞是 能够表现出适应性免疫记忆的属性。结果，她以前的工作使用了这些CMV- 特定的NK细胞和更经典的自适应CD8+ T细胞，进一步说明了这两个淋巴细胞 共享一个常见的转录和表观遗传记忆签名。从这个签名建造，她将磨练 关于两个候选转录因子Zeb2和JunB，以测试其对最佳效应函数的要求， 使用遗传鼠标模型，在两种单元格中的记忆形成，内存维护和回忆 暂时删除基因。使用高通量测序技术的组合，她将 生成全局转录组，表观基因组和转录因子占用率概况，以阐明 内存NK和CD8+ T细胞之间的任何常见机制。这项建议改善了我们的理解 抗病毒过程和免疫记忆力最终将其用于疫苗治疗和疾病 干涉。 在整个过渡期间，候选人将专注于推进她的技术和 生成和分析大型和复杂数据集的计算技能，改善和行使她 指导技能，通过定期参加科学研讨会和 会议，并发展她的授予写作技巧。她渴望获得终身教师职位，并 在她以前的导师的非正式指导下，努力执行她的长期研究计划 研究免疫记忆。