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: 10599971
• 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/10599971
• 关键词: Achievement; Advisory Committees; Amplifiers; Animals; Appointment; Arthritis; Autoimmune Diseases; Award; Biochemistry; Bioinformatics; Biology; Blocking Antibodies; Blood; Blood Platelets; Bone Marrow; Bone Marrow Cells; Boston; Cell Adhesion Molecules; Cell Communication; Cell Nucleus; Cells; Cellular Immunology; Chemotaxis; Circulation; 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; Institution; Interleukin-1 beta; International; K/BxN model; Knowledge; Laboratories; Large Megakaryocyte; Leadership; Learning; Marrow; Mass Spectrum Analysis; Mediating; Mediator; Megakaryocytes; Membrane; 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; cell behavior; eptifibatide; exosome; immune function; immunoregulation; 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.

项目摘要/摘要 这一K01奖项是为皮埃尔·库宁博士提供高级研究培训、保护时间和 导师需要成为一名独立的研究人员，专门从事活体双光子显微镜和 致力于了解巨核细胞作为免疫的直接调节器的作用。 候选人：库宁博士是哈佛医学院(波士顿马萨诸塞州)的儿科学讲师，在 波士顿儿童医院免疫科的彼得·尼格罗维奇博士。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 在细胞免疫学、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K01项目试图了解胚胎(EP)的功能，EP是一种细胞内细胞 中性粒细胞穿过巨核细胞细胞质的相互作用。常规观察到的 所有被检查的物种的骨髓，EP从未被深入的实验研究过。库宁博士 研究发现，EP在关节炎和其他形式的全身炎症中增加，表明在疾病中发挥了作用。他 先前报道，EP是一个活跃的、高度受调控的过程，介导着双向的 中性粒细胞和巨核细胞之间的蛋白质和膜。初步数据显示，此次交流 对中性粒细胞功能有重要的生理影响。库宁博士将评估EP是如何调节的 中性粒细胞在健康和炎症中的免疫功能。最后，库宁博士将找出 通过靶向中性粒细胞或巨核细胞来操纵EP，为治疗靶向开辟了可能性。 指导/培训：PI的长期目标是成为一名独立的调查员和终身教员 一流学术中心的成员。拟议的研究和培训计划将为库宁博士奠定基础 获得独立的R01资金，成为国际公认的行业前沿领导者 巨核细胞作为免疫细胞的探索，以及这个谱系在疾病中的病理作用 自身免疫性和炎症性疾病。他被任命为双光子设施的主任 BCH免疫学部门，他将成为观察免疫细胞的活体成像专家 在他们的器官中、在健康的动物身上或受到炎症影响的行为。他的研究训练将包括 活体细胞可视化和活细胞分析、动物外科和用于RNA测序的生物信息学。 此外，他还将学习实验室领导技能，以促进过渡到自己的实验室。这项工作 将在一流的机构环境中进行，并由彼得·尼格罗维奇博士指导，他是一名 髓系生物学和炎症性疾病，意大利博士，巨核细胞生物学专家，以及 顾问委员会，包括Bergmeier博士和Kim博士(手术和活体评估)。关于2-的指导意见 光子技术问题和RNAseq分析将由合作者Chen博士和Lee博士提供。