Molecular Programming of Immunological Memory in Human Natural Killer Cells

人类自然杀伤细胞免疫记忆的分子编程

• 批准号: 9514428
• 负责人: Frank Cichocki
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9514428
• 关键词: Acute; Address; Advisory Committees; Affect; Affinity; Antibodies; Antigens; B-Lymphocytes; Basic Science; Binding; Biometry; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Center; Cell Differentiation process; Cells; Cellular biology; Cessation of life; ChIP-seq; Characteristics; Clinical; Core Facility; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; DNA Methylation; Data; Disease; Down-Regulation; Embryonic Development; Embryopathy; Epigenetic Process; Exhibits; FCGR3B gene; Flow Cytometry; Formaldehyde; Frequencies; Future; Gene Expression; Generations; Genetic Transcription; Genomics; Goals; Grant; High-Throughput Nucleotide Sequencing; High-Throughput RNA Sequencing; Human; Immunocompetent; Immunoglobulin G; Immunologic Memory; Immunologist; Immunotherapy; In Vitro; Individual; Infection; Inflammatory; Informatics; Institution; Interleukin-12; Interleukin-15; Knowledge; Lead; Leukocytes; Life; Link; Lymphocyte; Memory; Mentors; Mentorship; Minnesota; Molecular; Molecular Biology; Morbidity - disease rate; Myelogenous; Natural Killer Cells; Newborn Infant; Organ; Pathway interactions; Phase; Phenotype; Physiological; Population; Positioning Attribute; Pregnancy; Primary Infection; Process; Regulatory Element; Relapse; Research; Research Activity; Research Personnel; Resource Sharing; Resources; STAT3 gene; STAT4 gene; Signal Transduction; Signaling Protein; Solid; Stat5 protein; Stem cell transplant; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Universities; Vaccines; Vascular blood supply; Viral; Viral Antigens; Work; ZNF145 gene; base; career; chromatin immunoprecipitation; chromatin remodeling; cytokine; design; experimental study; genome-wide; hematopoietic cell transplantation; infancy; interest; latent infection; leukemia; novel; prevent; programs; reactivation from latency; receptor; response; secondary infection; seropositive; success; transcription factor; transcriptome; tumor

 DESCRIPTION (provided by applicant): Project Summary Recent evidence suggests that natural killer (NK) cells can develop immunological memory against viral antigens. Our extensive preliminary data show that cytomegalovirus (CMV) infection is associated with the generation of novel populations of highly differentiated, adaptive NK cells. These NK cell subsets display a genome-wide DNA methylation profile that mirrors that of effector CD8+ T cells. In the present proposal, the applicant (Dr. Frank Cichocki) will study global epigenetic remodeling in CMV-induced adaptive NK cells using a high-throughput sequencing approach and will identify the factors that drive their proliferation and differentiation. Dr. Cichocki has assembled a team of experts from the University of Minnesota's Masonic Cancer Center (MMC) and outside institutions to guide the proposed research activities and provide mentorship during his transition to independence. In addition to direct support from mentors and an advisory committee, Dr. Cichocki will have full access to the shared resources available in the MMC. These include core facilities in flow cytometry, high-throughput sequencing and genomics, biostatistics, and informatics. Dr. Cichocki will continue in his mentored position for two years while analyzing epigenetic remodeling in CMV- induced adaptive NK cells; this work will allow him to gain further expertise in high-throughput sequencing technologies, which will be critical to the success of his future research career. As Dr. Cichocki transitions into the independent phase of his career, he will focus on hypothesis-driven experiments that are based on preliminary data showing that the combination of IL-15, IL-21, IL-12, and CD16 receptor engagement drive the expansion of CMV-induced adaptive NK cells. The data generated from the proposed studies will form the basis for an R01 application to be completed by year 3.5-4. The proposed studies are significant because they address a considerable gap in basic research that is needed to fully characterize adaptive NK cell subsets and understand the mechanisms that drive their differentiation and proliferation before they can be utilized in clinicl settings. These findings may have major clinical implications for the design of CMV vaccines that elicit NK cell memory and in the context of hematopoietic cell transplantation where CMV reactivation is associated with protection from leukemia relapse. Dr. Cichocki's long-term goal is to dedicate his career to advancing basic and translational NK cell biology as an independent investigator at an academic institution. As an immunologist with a deep interest and proven track record in molecular biology and epigenetics, he is in a unique position to answer the questions set forth in this proposal and to rapidly advance the mechanistic understanding of NK cell memory.

 描述（由申请人提供）：项目摘要最近的证据表明自然杀伤（NK）细胞可以形成针对病毒抗原的免疫记忆。我们广泛的初步数据表明，巨细胞病毒 (CMV) 感染与高度分化、适应性 NK 细胞的新群体的产生有关。这些 NK 细胞亚群显示出与效应 CD8+ T 细胞相似的全基因组 DNA 甲基化谱。在本提案中，申请人（Frank Cichocki 博士）将使用高通量测序方法研究 CMV 诱导的适应性 NK 细胞的整体表观遗传重塑，并确定驱动其增殖和分化的因素。 Cichocki 博士召集了来自明尼苏达大学共济会癌症中心 (MMC) 和外部机构的专家团队来指导拟议的研究活动，并在他向独立过渡期间提供指导。除了导师和咨询委员会的直接支持外，Cichocki 博士还将完全访问 MMC 中提供的共享资源。其中包括流式细胞术、高通量测序和基因组学、生物统计学和信息学方面的核心设施。 Cichocki 博士将继续担任他的指导职位两年，同时分析 CMV 诱导的适应性 NK 细胞的表观遗传重塑；这项工作将使他获得高通量测序技术方面的更多专业知识，这对于 他未来研究生涯的成功。随着 Cichocki 博士进入其职业生涯的独立阶段，他将专注于假设驱动的实验，这些实验基于初步数据，这些数据显示 IL-15、IL-21、IL-12 和 CD16 受体结合的结合可驱动 CMV 诱导的适应性 NK 细胞的扩增。拟议研究产生的数据将构成 3.5-4 年完成的 R01 申请的基础。拟议的研究意义重大，因为它们解决了基础研究中的巨大空白，需要充分表征适应性 NK 细胞亚群并了解驱动其分化和增殖的机制，然后才能将其用于临床环境。这些发现可能对引发 NK 细胞记忆的 CMV 疫苗的设计以及在造血细胞移植的背景下具有重大临床意义，其中 CMV 重新激活与防止白血病复发有关。 Cichocki 博士的长期目标是作为学术机构的独立研究者，致力于推进基础和转化 NK 细胞生物学的发展。作为一名对分子生物学和表观遗传学有着浓厚兴趣并拥有良好记录的免疫学家，他处于独特的地位来回答本提案中提出的问题，并迅速推进对 NK 细胞记忆机制的理解。