Investigating IL-10-producing suppressive NK cells

项目概要/摘要 博士Kristina Burrack的研究已经确定了一种细胞因子复合物治疗， 自然杀伤（NK）细胞产生免疫抑制细胞因子IL-10，并防止小鼠死于 一种免疫介导的疾病，由疟原虫感染引起，称为脑型疟疾。疟疾是一 这是一个严重的全球性健康问题，每年有超过2亿例临床病例和近50万例死亡。 脑型疟疾（CM）是疟原虫感染的一种致命并发症，主要影响儿童， 5岁，并可能导致存活儿童的长期神经功能缺损。在人类疾病中， 在脑型疟疾的小鼠模型中，病理性免疫反应被认为有助于破坏 血脑屏障在本提案中，Burrack博士将更全面地阐明细胞因子的作用， 复合物刺激的脑型疟疾中的NK细胞以及人和小鼠NK细胞中IL-10的诱导。在 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 在明尼苏达大学免疫学中心，包括流式细胞术的核心设施，动物 设施和生物统计。与明尼苏达大学Hennepin Healthcare合作者的互动 研究所，马约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 脑疟疾小鼠模型，这将是至关重要的，因为她过渡到她的独立阶段， 事业拟议研究产生的数据将构成R 01申请的基础。拟议 这些研究意义重大，因为它们解决了基础研究中的一个关键空白， 细胞因子刺激后的NK细胞活化-具体而言，如何诱导产生IL-10的抑制性NK细胞 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 人类脑型疟疾和其他疟疾的预防性治疗设计的临床意义 免疫病理学疾病和通知新的NK细胞定向疗法的发展。Burrack医生的 她的长期目标是致力于推进基础和转化免疫学和传染病 在学术机构担任独立研究员进行疾病研究。作为一名免疫学家， 对研究影响全球健康的传染病的发病机理有兴趣，并有良好的记录 重要的是，她处于一个独特的地位，可以回答这项建议中提出的问题，并迅速推进 了解如何调节NK细胞刺激以预防免疫病理学和IL-10的作用， 在脑型疟疾发病机制中产生NK细胞。

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.