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: 10217253
• 负责人: CRAIG N MORRELL
• 金额: $ 19.25万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217253
• 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.

项目总结

项目成果

Platelet and Megakaryocyte Roles in Innate and Adaptive Immunity.

• DOI: 10.1161/circresaha.121.319821
• 发表时间: 2022-01-21
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Koupenova M;Livada AC;Morrell CN
• 通讯作者: Morrell CN

β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.

• DOI: 10.1161/circresaha.120.317119
• 发表时间: 2021-03-05
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Hilt ZT;Maurya P;Tesoro L;Pariser DN;Ture SK;Cleary SJ;Looney MR;McGrath KE;Morrell CN
• 通讯作者: Morrell CN