Platelet-Regulated Immune Responses in Neonates Following Transfusion

项目摘要 该提案汇集了Palis和Morrell实验室在发展方面的专业知识， 造血和血小板生物学，分别，以获得一个机制的理解， 新生儿血小板输注相关并发症。血小板减少症常见于 新生儿，特别是早产儿。血小板输注可用于预防 出血，但最近的临床研究表明，血小板输注给新生儿，而也许 减少出血风险，可能会增加严重的，有时是长期的并发症，包括 视网膜病变、坏死性小肠结肠炎和败血症。因此，我们寻求更好地了解这些机制， 导致这些血小板介导的不良后果。我们的长期目标是减轻他们的不利影响， 血小板输注的影响，并最终开发出体外修饰的血小板，包括血小板衍生的 从诱导多能干细胞（iPS），以提高新生儿输血治疗的安全性。 我们已经发现，与成人血小板相比，新生儿血小板差异表达几种 免疫相关分子。这些数据导致我们的总体假设，即输注成人血小板 进入新生儿驱动单核细胞中的炎性表型，导致不良并发症。这 我们利用新的鼠新生儿输血模型的初步数据进一步支持了这一假设， 其中单核细胞炎性反应被成人血小板输注增强，但未被新生儿血小板输注增强。 我们将利用这种体内模型来定义血小板驱动的免疫反应，重点是致病作用， 血小板衍生的免疫介质在单核细胞的激活在体外和体内。最后为 为了更深入地了解成人与新生儿血小板的发育程序，我们将 启动小鼠和人类血小板转录组和蛋白质组的比较研究，重点是 免疫相关分子的差异表达。 该项目的完成将建立关于发育生物学的基本见解， 血小板及其与新生儿免疫系统相互作用的能力。这一知识将奠定 为未来研究重新编程血小板免疫功能以提高安全性和有效性奠定基础 新生儿和成人的血小板输注。

Project Summary This proposal brings together the expertise of the Palis and Morrell labs in developmental hematopoiesis and platelet biology, respectively, in order to gain a mechanistic understanding of the complications associated with platelet transfusions into neonates. Thrombocytopenia is common in newborns, particularly in premature infants. Platelet transfusions are prophylactically used to prevent bleeding, but recent clinical studies have shown that the transfusion of platelets to neonates, while perhaps reducing bleeding risk, can increase serious and sometimes long-term complications including retinopathies, necrotizing enterocolitis and sepsis. We therefore seek to better understand the mechanisms that contribute to these platelet-mediated adverse outcomes. Our long-term aim is to mitigate their adverse effects of platelet transfusions and ultimately develop ex vivo modified platelets, including platelets derived from induced pluripotent stem (iPS) cells, to increase the safety of transfusion therapy for neonates. We have discovered that, compared to adult platelets, neonatal platelets differentially express several immune-related molecules. These data lead to our overall hypothesis that the transfusion of adult platelets into neonates drives an inflammatory phenotype in monocyte leading to adverse complications. This hypothesis is further supported by our preliminary data utilizing a novel murine neonatal transfusion model, where monocyte inflammatory responses were enhanced by adult, but not neonatal, platelet transfusions. We will utilize this in vivo model to define platelet-driven immune responses, focusing on the causative role of platelet-derived immune mediators in the activation of monocytes both in vitro and in vivo. Finally, to obtain a deeper understanding of the developmental program of adult versus neonatal platelets, we will initiate comparative studies of murine and human platelet transcriptomes and proteomes, focusing on the differential expression of immune-related molecules. Completion of this project will establish fundamental insights regarding the developmental biology of platelets and their ability to interact with the immune system of neonates. This knowledge will lay the groundwork for future studies in re-programming platelet immune functions to improve safety and efficacy of platelet transfusions both for neonates and adults.