Transcriptional regulation of immunological memory in innate and adaptive lymphocytes

项目总结 候选人刘慧琳博士寻求以独立研究的方式实现学术生涯 在一家机构担任研究员，在那里她可以促进学术发展和推动免疫学研究 人类疾病的治疗或预防。她的目标是通过实验室实验的联合来实现这一点 和生物信息学方法，这反映在她目前的提案中。 她的项目旨在了解推动免疫系统正常形成的潜在机制。 在病毒感染的背景下，用小鼠在两个溶细胞淋巴细胞中研究它的记忆 以巨细胞病毒(CMV)为模型。通过研究老鼠的感染，以前在实验室中进行的工作已经 证明了自然杀伤(NK)细胞，传统上被归类为天然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。因此，她之前的工作使用了这些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 共享共同的转录和表观遗传记忆签名。在这个签名的基础上，她将磨练 在两个候选转录因子ZEB2和JunB上测试它们对最佳效应器功能的要求， 两种细胞类型的记忆形成、记忆维持和回忆，使用的遗传小鼠模型 暂时删除该基因。使用高通量测序技术的组合，她将 生成全球转录组、表观基因组和转录因子占有率曲线，以便阐明 记忆性NK细胞和CD8 T细胞之间的共同机制。这项建议提高了我们的认识 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 干预。 在整个过渡和获奖期间，候选人将专注于提高她的技术和 生成和分析大型复杂数据集的计算技能，改进和锻炼HER 指导技能，通过定期参加科学研讨会和 会议，并发展她的赠款写作技能。她渴望获得一个终身教职的职位，而且， 在她以前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。

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.