Platelet-Regulated Immune Responses in Neonates Following Transfusion

新生儿输血后血小板调节的免疫反应

• 批准号: 10039184
• 负责人: CRAIG N MORRELL
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039184
• 关键词: Adult; Adverse effects; Affect; Biological Response Modifiers; Biology; Birth Weight; Blood Platelets; Clinical Research; Comparative Study; Data; Development; Developmental Biology; Future; Goals; Hematopoiesis; Hematopoietic; Hemorrhage; Human; Immune; Immune response; Immune system; In Vitro; Infant; Inflammatory; Inflammatory Response; Knowledge; Lead; Mediating; Modeling; Mus; Necrotizing Enterocolitis; Neonatal; Newborn Infant; Phenotype; Platelet Transfusion; Premature Infant; Proteins; Proteome; Retinal Diseases; Risk; Role; Safety; Sepsis; Signal Transduction; Testing; Thrombocytopenia; Transforming Growth Factor alpha; Transfusion; adverse outcome; differential expression; immune function; improved; in vivo; in vivo Model; in vivo evaluation; induced pluripotent stem cell; insight; monocyte; neonate; novel; prevent; programs; prophylactic; response; trafficking; transcriptome

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.

项目摘要 该提议汇集了Palis和Morrell实验室的专业知识 造血和血小板生物学分别为了获得对机械的理解 与血小板输入新生儿有关的并发症。血小板减少症很常见 新生儿，特别是在早产婴儿中。血小板输血可预防以防止 出血，但最近的临床研究表明，血小板向新生儿输血，而可能 降低出血风险，会增加严重的，有时甚至是长期的并发症，包括 视网膜病，坏死性小肠结肠炎和败血症。因此，我们寻求更好地了解机制 这有助于这些血小板介导的不良结果。我们的长期目标是减轻他们的不利 血小板输血的作用并最终发展出体内修饰的血小板，包括衍生的血小板 从诱导的多能干（IPS）细胞，以提高新生儿输血治疗的安全性。 我们发现，与成年血小板相比，新生儿血小板差异表达了几种 免疫相关分子。这些数据导致了我们的总体假设，即成人血小板的输血 进入新生儿会在单核细胞中驱动炎症表型，导致不良并发症。这 利用新型鼠新生儿输血模型，我们的初步数据进一步支持了假设， 成人但没有新生儿血小板输血增强了单核细胞炎症反应的地方。 我们将利用这种体内模型来定义血小板驱动的免疫反应，重点是因果关系 血小板衍生的免疫介质在体外和体内激活中。最后，到 获得对成人与新生儿血小板的发展计划的更深入的了解，我们将 开始对鼠和人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有关有关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。这些知识将为 将来研究重新编程血小板免疫功能的基础工作，以提高安全性和功效 新生儿和成人的血小板输血。