Trans-megakaryocyte migration as neutrophil amplifier

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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.