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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：
8879873
负责人：
Frank Cichocki
金额：
$ 9.52万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879873
关键词：
Acute Acute Promyelocytic Leukemia Address Advisory Committees Affect Affinity Antibodies Antigens B-Lymphocytes Basic Science Binding Biometry CD8B1 gene Cancer Center Cell Differentiation process Cells Cellular biology Cessation of life ChIP-seq Characteristics Child 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 Gene Expression Profile Generations 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 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 Zinc Fingers base career chromatin immunoprecipitation chromatin remodeling cytokine design genome-wide hematopoietic cell transplantation infancy interest latent infection leukemia novel prevent programs receptor research study response secondary infection seropositive success transcription factor 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.