Investigating IL-10-producing suppressive NK cells

研究产生 IL-10 的抑制性 NK 细胞

基本信息

批准号：
9890636
负责人：
Kristina Stoermer Burrack
金额：
$ 16.2万
依托单位：
HENNEPIN HEALTHCARE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890636
关键词：
Address Age Antibodies Autoimmunity Basic Science Biological Biometry CD8-Positive T-Lymphocytes Cell physiology Cells Cerebral Malaria Cerebrovascular system Cerebrum Cessation of life Child Clinic Clinical Communicable Diseases Complex Complication Core Facility Cytoprotection Data Development Disease Endothelial Cells Flow Cytometry Foundations Goals Health Care Research Human Immune Immune response Immunity Immunologist Immunology Infection Infectious Diseases Research Institution Interleukin-10 Interleukin-15 Knockout Mice Knowledge Malaria Mediating Mentors Minnesota Modeling Molecular Analysis Mouse Strains Mus NK Cell Activation Natural Killer Cells Neurologic Deficit Outcome Parasites Pathogenesis Pathologic Pathology Pharmacology Phase Plasmodium berghei Population Positioning Attribute Production Reporting Research Research Institute Research Personnel Resource Sharing Role STAT3 gene Signal Pathway Signal Transduction T cell regulation T cell response T-Lymphocyte Therapeutic Universities Work animal facility base blood-brain barrier disruption cancer immunotherapy career cell type cellular targeting cytokine cytotoxic design global health human disease immunopathology inhibitor/antagonist interest knockout gene mouse model novel novel strategies novel therapeutic intervention pathogen prevent prophylactic protective effect receptor response tumor growth vaccine immunotherapy

项目摘要

PROJECT SUMMARY/ABSTRACT Dr. Kristina Burrack’s research has led to the identification of a cytokine complex treatment that stimulates natural killer (NK) cells to produce the immunosuppressive cytokine IL-10 and prevents mice from dying from an immune-mediated disease following Plasmodium infection known as cerebral malaria. Malaria is a significant global health problem with more than 200 million clinical cases and nearly 500,000 deaths annually. Cerebral malaria (CM) is a deadly complication of Plasmodium infection that mostly afflicts children under the age of five and can result in long-term neurologic deficits in children who survive. In the human disease and the mouse model of cerebral malaria, a pathologic immune response is thought to contribute to disruption of the blood brain barrier. In the present proposal, Dr. Burrack will more fully elucidate the role of cytokine complex-stimulated NK cells in cerebral malaria and the induction of IL-10 in human and mouse NK cells. In addition to direct support from mentors and collaborators, Dr. Burrack has full access to the shared resources in the Center for Immunology at the University of Minnesota, including core facilities in flow cytometry, animal facilities, and biostatistics. Interactions with collaborators at the University of Minnesota, Hennepin Healthcare Research Institute, the Mayo Clinic, and elsewhere will allow her to gain further expertise in the analysis of molecular signaling pathways, analyze human NK cells, generate new mouse strains, and further investigate the cerebral malaria mouse model, which will be critical as she transitions into the independent phase of her career. The data generated from the proposed studies will form the basis for an R01 application. The proposed studies are significant because they address a critical gap in basic research that is needed to fully characterize NK cell activation following cytokine stimulation – specifically, how to induce IL-10-producing suppressive NK cells – and understand the mechanisms that prevent fatal immunopathology. These findings will have major clinical implications for the design of adjunctive therapies for human cerebral malaria and other immunopathologic diseases and inform the development of novel NK cell-directed therapies. Dr. Burrack’s long-term goal is to dedicate her career to advancing basic and translational immunology and infectious disease research as an independent investigator at an academic institution. As an immunologist with a deep interest and proven track record in studying the pathogenesis of infectious diseases of global health importance, she is in a unique position to answer the questions set forth in this proposal and to rapidly advance the understanding of how to tune NK cell stimulation to prevent immunopathology and the role of IL-10- producing NK cells in the pathogenesis of cerebral malaria.

项目概要/摘要克里斯蒂娜·伯拉克 (Kristina Burrack) 博士的研究发现了一种细胞因子复合物治疗方法，可刺激自然杀伤 (NK) 细胞产生免疫抑制细胞因子 IL-10 并防止小鼠死亡疟原虫感染后的一种免疫介导疾病，称为脑型疟疾。严重的全球健康问题，每年有超过 2 亿临床病例和近 50 万人死亡。脑型疟疾 (CM) 是疟原虫感染的一种致命并发症，主要影响 10 岁以下的儿童。五岁时，可能会导致幸存儿童的长期神经功能缺陷。在脑型疟疾小鼠模型中，病理性免疫反应被认为有助于破坏在目前的提案中，Burrack 博士将更全面地阐明细胞因子的作用。脑型疟疾中复合物刺激的 NK 细胞以及人类和小鼠 NK 细胞中 IL-10 的诱导。除了导师和合作者的直接支持外，Burrack 博士还可以完全访问共享资源明尼苏达大学免疫学中心，包括流式细胞术、动物设施和生物统计学与明尼苏达大学亨内平医疗保健中心的合作者的互动。研究所、梅奥诊所和其他地方将使她获得进一步的专业知识分析分子信号通路，分析人类 NK 细胞，产生新的小鼠品系，并进一步研究脑型疟疾小鼠模型，这对于她过渡到其独立阶段至关重要拟议研究产生的数据将构成 R01 申请的基础。研究意义重大，因为它们解决了基础研究中的一个关键差距，而基础研究需要充分表征细胞因子刺激后 NK 细胞激活——具体来说，如何诱导产生 IL-10 的抑制性 NK 细胞——并了解预防致命免疫病理学的机制，这些发现将具有重大意义。对人类脑型疟疾和其他疾病辅助疗法设计的临床意义 Burrack 博士的免疫病理学疾病并为新型 NK 细胞导向疗法的开发提供信息。长期目标是致力于推进基础和转化免疫学以及传染病学作为学术机构的独立调查员进行疾病研究。对研究全球健康传染病发病机制的兴趣和良好的记录重要性，她处于独特的地位来回答该提案中提出的问题并迅速推进了解如何调整 NK 细胞刺激以预防免疫病理学以及 IL-10- 的作用脑型疟疾发病机制中产生 NK 细胞。