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.

项目概要 候选人 Colleen Lau 博士寻求以独立研究的方式实现学术生涯 一家机构的研究员，她可以在那里促进学术发展和免疫学研究的进步 治疗或预防人类疾病。她的目标是通过实验室实验的结合来实现这一目标 和生物信息学方法，正如她当前的提案所反映的那样。 她的项目旨在了解驱动免疫正确形成的潜在机制 通过在病毒感染的情况下研究两个溶细胞淋巴细胞的记忆，使用小鼠 巨细胞病毒（CMV）作为模型。通过研究小鼠的感染，之前在实验室进行的工作已经 证明自然杀伤 (NK) 细胞（传统上被归类为先天细胞的溶细胞淋巴细胞） 能够表现出适应性免疫记忆的属性。结果，她之前的工作就用了这些CMV- 特异性NK细胞和更经典的适应性CD8+T细胞进一步说明这两种淋巴细胞 具有共同的转录和表观遗传记忆特征。以此签名为基础，她将磨练 对两个候选转录因子ZEB2和JunB进行测试，以测试它们对最佳效应子功能的要求， 使用遗传小鼠模型，两种细胞类型的记忆形成、记忆维持和回忆 暂时删除该基因。结合使用高通量测序技术，她将 生成全局转录组、表观基因组和转录因子占用图谱，以阐明 记忆 NK 和 CD8+ T 细胞之间的任何共同机制。这个建议增进了我们的理解 抗病毒过程和免疫记忆，以便最终将其用于疫苗治疗和疾病 干涉。 在整个过渡和奖励期间，候选人将专注于提高她的技术和能力 生成和分析大型复杂数据集的计算技能，提高和锻炼她 指导技能，通过定期参加科学研讨会来拓宽她的科学背景， 会议，并发展她的资助写作技巧。她渴望获得终身教职，并且， 在她以前的导师的非正式指导下，努力开展她的长期研究计划 研究免疫记忆。