Effects of Platelet Transfusions on Neonatal Chronic Lung Disease and Sepsis-Induced Mortality

血小板输注对新生儿慢性肺病和败血症所致死亡率的影响

• 批准号: 10621867
• 负责人: Patricia Ellen Davenport
• 金额: $ 20.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621867
• 关键词: Admission activity; Adult; Advisory Committees; Affect; Award; Awareness; Biology; Birth; Blood; Blood Cells; Blood Platelets; Boston; Bronchopulmonary Dysplasia; CXCL1 gene; CXCL5 gene; Cell Communication; Cells; Cessation of life; Chemotactic Factors; Child; Chronic lung disease; Clinical; Clinical Research; Coagulation Process; Communicable Diseases; Complication; Data; Dedications; Development; Disease; Endotoxemia; Environment; European; Extremely Low Birth Weight Infant; Functional disorder; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hematology; Hemorrhage; Hemostatic function; Host Defense; Hour; Human; Human Biology; Hyperoxia; IL17 gene; Immune; Immune system; Immunology; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-6; Knowledge; Laboratories; Link; Lung; Lung diseases; Macrophage; Manuscripts; Mediating; Medicine; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mus; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Neonatal Thrombocytopenia; Neonatology; Newborn Infant; Observational Study; Organ; Oxygen; Participant; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Physicians; Physiology; Planets; Plasma; Platelet Count measurement; Platelet Transfusion; Premature Infant; Process; Productivity; Publishing; Pulmonary Inflammation; Randomized; Research; Research Design; Research Personnel; Resources; Risk; Role; Scientist; Sepsis; Severities; Stimulus; Surveys; Testing; Thrombocytopenia; Time; Training; Transfusion; Umbilical Cord Blood; United States National Institutes of Health; Vulnerable Populations; Writing; career; career development; clinical practice; clinically relevant; cytokine; design; experimental study; high risk; improved; improved outcome; insight; lung injury; medical schools; meetings; mortality; mouse model; neonatal human; neonatal infection; neonatal mice; neonatal morbidity; neonatal sepsis; neonate; neutrophil; polymicrobial sepsis; postnatal; premature; preterm newborn; prevent; primary outcome; pulmonary function; randomized trial; response; secondary outcome; statistics; success; synergism; systemic inflammatory response; training opportunity; transfusion medicine

SUMMARY This K99/R00 proposal describes a five-year mentored research and training plan that will facilitate the transition of Dr. Patricia Davenport to an independent academic researcher in neonatal hematology. Dr. Davenport is a productive and dedicated young physician-scientist working in a clinically relevant and understudied field. PLTs are active participants in both hemostasis and inflammation, yet clinical awareness of these dual roles has lagged behind research discoveries, particularly in neonatology. Preterm infants are at high risk of spontaneous bleeding (particularly intracranial) and thus are typically transfused at higher PLT counts than children or adults, in the hope of preventing bleeding. However, a recent large randomized trial in preterm neonates found that liberal PLT transfusions increased mortality and risk of chronic lung disease, without decreasing bleeding. The mechanisms mediating these findings are unknown, but we hypothesize that they are at least partly related to the developmental differences between neonatal and adult PLTs. The overarching aim of this proposal is to improve the management of neonatal thrombocytopenia through a better understanding of the consequences of PLT transfusions in neonates with various underlying pathologies. Our overall hypothesis is that the effects of PLT transfusions increasing neonatal mortality and severity of chronic lung disease are mediated by an amplification of the neonatal inflammatory responses. To test this hypothesis, we designed the following Specific Aims: 1. Determine the effects of PLT transfusions on newborn mice with and without endotoxemia; 2. Determine the effects of PLT transfusions on mortality in a neonatal model of sepsis; and 3. Characterize the effects of PLT transfusions in a neonatal murine model of chronic lung disease. This research is highly significant, as knowledge gained from it will inform clinical practice and research. Dr. Davenport will receive mentorship from her co- mentors, Dr. Martha Sola-Visner, an NIH-funded researcher in the field of neonatal PLT biology, and Dr. Stella Kourembanas, a world-renowned investigator in neonatal pulmonary physiology and chronic lung disease. In addition, Dr. Davenport will have the guidance of her Scientific Advisory Committee, composed of distinguished scientists with expertise in transfusion medicine and immunology, neonatal sepsis and inflammation, infectious diseases, and study design/statistics. The training opportunities and resources at Boston Children’s Hospital (BCH) and Harvard Medical School provide an ideal environment for the candidate’s career development. The Division of Newborn Medicine at BCH is committed to Dr. Davenport’s success and has assured at least 75% protected time to devote to the activities described in this proposal. A detailed career development and training plan is presented, including mentored research, didactic coursework, seminars and presentations at scientific meetings, and a plan for manuscript writing and R00 submission. The expertise and knowledge gained from this Award will enable Dr. Davenport to obtain future R01 funding and transition to an independent research career focusing on neonatal PLT biology, and particularly the interactions of PLTs with the neonatal lung.

概括 该K99/R00提案描述了一项为期五年的研究和培训计划，该计划将有助于过渡 帕特里夏·达文波特（Patricia Davenport）博士担任新生儿血液学的独立学术研究员。达文波特博士是 在临床相关和知识的领域中工作的生产力和专门的年轻身体科学家。 PLT 是止血和感染的积极参与者，但对这些双重角色的临床意识滞后 研究发现的背后，特别是在新生儿学方面。早产婴儿的赞助风险很高 （尤其是颅内），因此通常以比儿童或成人更高的PLT计数输出，在 希望防止流血。但是，最近一次在早产新生儿中进行的大型随机试验发现自由主义者 PLT输血增加了死亡率和慢性肺部疾病的风险，而不会减少出血。 介导这些发现的机制尚不清楚，但我们假设它们至少与 新生儿和成人PLT之间的发育差异。该提议的总体目的是 通过更好地理解后果，改善新生儿血小板减少症的管理 具有各种潜在病理的新生儿中的PLT输血。我们的总体假设是 引起新生儿死亡率和慢性肺病严重程度的PLT输血介导 新生儿炎症反应的扩增。为了检验这一假设，我们设计了以下特定 目的：1。确定PLT输血对患有和没有内毒素血症的新生小鼠的影响； 2。确定 PLT输血对败血症新生儿模型中死亡率的影响；和3。表征PLT的影响 慢性肺疾病的新生儿鼠模型中的输血。这项研究非常重要，因为知识 从中获得的将为临床实践和研究提供依据。 Davenport博士将从她的共同 导师，NIH资助的新生儿PLT生物学领域的NIH资助的研究员Martha Sola-Visner博士和Stella博士 Kourembanas是新生儿肺部生理学和慢性肺部疾病的世界知名研究者。在 此外，Davenport博士将由其科学咨询委员会的指导，由杰出的委员会组成 具有输血医学和免疫学专业知识的科学家，新生儿败血症和炎症，感染力 疾病和研究设计/统计。波士顿儿童医院的培训机会和资源 （BCH）和哈佛医学院为候选人的职业发展提供了理想的环境。这 BCH的新生儿分部致力于达文波特博士的成功，并至少承担了75％ 保护时间用于投入本提案中描述的活动。详细的职业发展和培训 提出了计划，包括在科学的研究，教学课程，半学院和演讲 会议，以及手稿写作计划和R00提交的计划。从中获得的专业知识和知识 奖项将使Davenport博士能够获得未来的R01资金并过渡到独立研究职业 专注于新生儿PLT生物学，尤其是PLT与新生儿肺的相互作用。

项目成果

Quantitative label-free mass spectrometry reveals content and signaling differences between neonatal and adult platelets.

定量无标记质谱揭示了新生儿和成人血小板的含量和信号差异。

• DOI: 10.1016/j.jtha.2023.12.022
• 发表时间: 2023
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Thom,ChristopherS;Davenport,Patricia;Fazelinia,Hossein;Soule-Albridge,Erin;Liu,Zhi-Jian;Zhang,Haorui;Feldman,HenryA;Ding,Hua;Roof,Jennifer;Spruce,LynnA;Ischiropoulos,Harry;Sola-Visner,Martha
• 通讯作者: Sola-Visner,Martha

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm.

• DOI: 10.1001/jamanetworkopen.2023.52394
• 发表时间: 2024-01-02
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Davenport PE;Wood TR;Heagerty PJ;Sola-Visner MC;Juul SE;Patel RM
• 通讯作者: Patel RM