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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：项目摘要最近的证据表明，天然杀手（NK）细胞可以针对病毒抗原产生免疫记忆。我们广泛的初步数据表明，巨细胞病毒（CMV）感染与高度分化的自适应NK细胞的新型种群的产生有关。这些NK细胞子集显示出全基因组DNA甲基化谱，该甲基化曲线反映了效应CD8+ T细胞的甲基化谱。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诱导的自适应NK细胞中的全球表观遗传重塑，并将确定驱动其增殖和分化的因素。 Cichocki博士召集了明尼苏达大学共济会癌症中心（MMC）和外部机构的专家团队，以指导拟议的研究活动，并在其过渡到独立性期间提供精神训练。除了导师和咨询委员会的直接支持外，Cichocki博士还可以完全访问MMC中可用的共享资源。这些包括流式细胞仪，高通量测序和基因组学，生物统计学和信息的核心设施。 Cichocki博士将继续他的指导地位两年，同时分析CMV诱导的自适应NK细胞中的表观遗传重塑。这项工作将使他能够在高通量测序技术方面获得进一步的专业知识，这对他未来研究生涯的成功。随着Cichocki博士转变为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，表明IL-15，IL-21，IL-12和CD16受体参与的组合促进了CMV诱导的适应性NK细胞的扩展。从拟议的研究中产生的数据将构成R01应用程序在3.5 - 4年完成的基础。拟议的研究很重要，因为它们解决了基础研究中所需的考虑差距，以充分表征适应性的NK细胞亚群，并了解在临床环境中使用它们之前推动其分化和增殖的机制。这些发现可能对引起NK细胞记忆的CMV疫苗的设计具有主要的临床意义，并且在造血细胞移植的背景下，CMV重新激活与白血病的保护有关。 Cichocki博士的长期目标是将自己的职业生涯献给学术机构的独立研究者，推进基本和转化的NK细胞生物学。作为一名具有深厚兴趣和验证的分子生物学和表观遗传学记录的免疫学家，他处于一个独特的位置，可以回答该提案中提出的问题并迅速提高对NK细胞记忆的机械理解。