Trans-megakaryocyte migration as neutrophil amplifier

作为中性粒细胞放大器的跨巨核细胞迁移

• 批准号: 10449496
• 负责人: Pierre Cunin
• 金额: $ 12.73万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449496
• 关键词: Achievement; Advisory Committees; Amplifiers; Animals; Appointment; Arthritis; Autoimmune; Award; Biochemistry; Bioinformatics; Biology; Blocking Antibodies; Blood; Blood Circulation; Blood Platelets; Bone Marrow; Bone Marrow Cells; Boston; Cell Adhesion Molecules; Cell Communication; Cell Nucleus; Cells; Cellular Immunology; Chemotaxis; Confocal Microscopy; Cytoplasm; Data; Deposition; Disease; Electron Microscopy; Emperipolesis; Endothelial Cells; Endothelium; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Faculty; Flow Cytometry; Frequencies; Funding; Goals; Health; Hemostatic function; Human Biology; Hybrids; Imaging Device; Immune; Immunity; Immunology; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; International; K/BxN model; Knowledge; Laboratories; Large Megakaryocyte; Leadership; Learning; Marrow; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Megakaryocytes; Membrane; Membrane Proteins; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Microscopy; Modeling; Molecular; Molecular Biology; Mus; Myelogenous; Neutrophil Activation; Operative Surgical Procedures; Organ; Pathologic; Pediatric Hospitals; Pediatrics; Peritonitis; Photons; Physiological; Plasma; Positioning Attribute; Process; Proteins; Reporting; Research; Research Personnel; Research Training; Role; Route; Serum; Slide; Source; Speed; Sterility; TNF gene; Technical Expertise; Testing; Time; Training; Transgenic Mice; Visualization; Work; animal imaging; cell behavior; eptifibatide; exosome; immune function; in vivo; inhibitor; instructor; intravital imaging; intravital microscopy; medical schools; member; migration; neutrophil; novel; septic; skills; systemic inflammatory response; therapeutic target; training opportunity; transcriptome sequencing; two photon microscopy; two-photon

Project summary / abstract This K01 award is to provide Dr. Pierre Cunin with the advanced research training, protected time, and mentoring needed to become an independent investigator specialized in intravital 2-photon microscopy and committed to understanding the role of megakaryocytes as a direct modulators of immunity. Candidate: Dr. Cunin is an Instructor in Pediatrics at Harvard Medical School (Boston MA), in the laboratory of Dr. Peter Nigrovic in the Division of Immunology at the Boston Children’s Hospital. Dr Cunin’s previous training has provided him with extensive knowledge in the biology of human and murine immune cells, as well as a technical expertise in cellular immunology, molecular biology, biochemistry, and murine experimentation. Research: Dr. Cunin’s K01 project seeks to understand the function of emperipolesis (EP), a cell-in-cell interaction wherein a neutrophil transits through the cytoplasm of a megakaryocyte. Routinely observed in bone marrow from all species examined, EP had never been investigated in depth experimentally. Dr. Cunin found that EP increases in arthritis and other forms of systemic inflammation, suggesting a role in disease. He previously reported that EP is an active and highly regulated process that mediates bi-directional transfer of proteins and membrane between neutrophils and megakaryocytes. Preliminary data show that this exchange has important physiological consequences for neutrophil function. Dr. Cunin will evaluate how EP modulates the immune function of neutrophils in health and with inflammation. Finally, Dr. Cunin will identify ways to manipulate EP via targets on neutrophil or megakaryocyte, opening up the possibility of therapeutic targeting. Mentoring/Training: The long-term goal of the PI is becoming an independent investigator and tenured faculty member at a leading academic center. The proposed studies and training plan will set the stage for Dr. Cunin to obtain independent R01 funding and become an internationally recognized leader at the cutting-edge of the exploration of megakaryocytes as immune cells, as well as of the pathological role of this lineage in autoimmune and inflammatory diseases. With his appointment as Director of the 2-photon facility in the Division of Immunology at BCH, he will become an expert in intravital imaging to observe immune cells behaviors in their organs, in healthy animals or subjected to inflammation. His research training will encompass in vivo cell visualization and live cell analysis, animal surgery, and bioinformatics for RNA sequencing. Additionally, he will learn laboratory leadership skills to facilitate the transition to his own laboratory. The work will be performed in a superb institutional environment with the mentorship of Dr. Peter Nigrovic, an expert in myeloid biology and inflammatory diseases, Dr. Italiano, an expert in megakaryocyte biology, as well as an Advisory Committee including Drs. Bergmeier and Kim (surgery and in vivo assessment). Guidance on 2- photon technical issues and RNAseq analysis will be provided by collaborators Drs. Chen and Lee.

项目概要/摘要 这个K 01奖是为皮埃尔·库宁博士提供先进的研究培训，保护时间， 指导需要成为一个独立的研究者专门在活体2光子显微镜， 致力于了解巨核细胞作为免疫直接调节剂的作用。 候选人：Cunin博士是哈佛医学院（马萨诸塞州波士顿）的儿科讲师， 博士波士顿儿童医院免疫科的Peter Nigrovic说。库宁博士之前的训练 为他提供了人类和小鼠免疫细胞生物学方面的广泛知识，以及 细胞免疫学、分子生物学、生物化学和小鼠实验方面的技术专长。 研究：库宁博士的K 01项目旨在了解帝国主义（EP）的功能，这是一种细胞中的细胞。 嗜中性粒细胞穿过巨核细胞的细胞质的相互作用。观察到， 从所有物种的骨髓检查，EP从未进行过深入的实验研究。库宁医生 发现EP在关节炎和其他形式的全身性炎症中增加，表明在疾病中的作用。他 先前报道，EP是一个活跃的和高度调节的过程，介导双向转移， 中性粒细胞和巨核细胞之间的蛋白质和膜。初步数据显示， 对中性粒细胞功能具有重要的生理影响。Cunin医生将评估EP如何调节 中性粒细胞的免疫功能在健康和炎症中的作用。最后，Cunin博士将找出方法， 通过靶向中性粒细胞或巨核细胞操纵EP，开辟了治疗靶向的可能性。 指导/培训：PI的长期目标是成为独立的研究者和终身教职员工 在一个领先的学术中心的成员。拟议的研究和培训计划将为Cunin博士奠定基础。 获得独立的R 01资金，并成为国际公认的前沿领导者。 探索巨核细胞作为免疫细胞，以及这一谱系在免疫系统中的病理作用。 自身免疫性和炎症性疾病。随着他被任命为2010年2光子设施的主任， 他将成为活体成像观察免疫细胞的专家 行为在他们的器官，在健康的动物或受到炎症。他的研究训练将包括 体内细胞可视化和活细胞分析、动物手术和用于RNA测序的生物信息学。 此外，他将学习实验室领导技能，以促进过渡到自己的实验室。工作 将在一个极好的机构环境中进行，由Peter Nigrovic博士指导，他是一位专家， 骨髓生物学和炎症性疾病，Italiano博士，巨核细胞生物学专家，以及 咨询委员会包括Bergmeier和Kim博士（手术和体内评估）。指导2- 光子技术问题和RNAseq分析将由合作者Chen和Lee博士提供。