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

摘要 这份K99/R00提案描述了一项五年指导研究和培训计划，该计划将促进过渡 帕特里夏·达文波特博士成为新生儿血液学的独立学术研究员。达文波特博士是一位 在临床相关和研究不足的领域工作的富有成效和敬业精神的年轻内科科学家。PLTS 都是止血和炎症的积极参与者，但临床上对这两个角色的认识一直滞后 研究发现的背后，特别是在新生儿学方面。早产儿自发性出血的风险很高 (尤其是颅内)，因此通常比儿童或成人输血时的PLT计数更高。 希望能防止出血。然而，最近一项针对早产儿的大型随机试验发现，自由派 输注PLT会增加死亡率和慢性肺部疾病的风险，但不会减少出血。这个 调解这些发现的机制尚不清楚，但我们假设它们至少部分与 新生儿与成人PLT的发育差异。这项建议的主要目的是 通过更好地了解新生儿血小板减少的后果，改善对新生儿血小板减少的管理 有各种潜在病理的新生儿输注PLT。我们的总体假设是， 血小板输注增加新生儿死亡率和慢性肺部疾病的严重程度是由 放大新生儿炎症反应。为了验证这一假设，我们设计了以下具体的 目的：1.测定血小板输注对新生小鼠内毒素血症和非内毒素血症的影响；2.测定 输注PLT对新生儿败血症模型死亡率的影响；以及3.描述PLT的影响 慢性肺病新生小鼠模型的输血。作为知识，这项研究具有很高的意义 从中获得的信息将为临床实践和研究提供参考。达文波特博士将接受她的合作伙伴的指导- 导师，美国国立卫生研究院资助的新生儿PLT生物学领域的研究人员Martha Sola-Visner博士和Stella博士 库伦巴纳斯，世界著名的新生儿肺生理学和慢性肺部疾病的研究人员。在……里面 此外，达文波特博士将得到她的科学咨询委员会的指导，该委员会由杰出的 在输血医学和免疫学、新生儿败血症和炎症、感染性疾病方面有专长的科学家 疾病，以及研究设计/统计。波士顿儿童医院的培训机会和资源 (BCH)和哈佛医学院为求职者的职业发展提供了理想的环境。这个 BCH的新生儿医学部致力于达文波特博士的成功，并已确保至少75% 受保护的时间投入到本提案所述的活动中。详细的职业发展和培训 提出计划，包括有指导的研究、教学课程、研讨会和科学报告。 会议，以及手稿写作和R00提交计划。从这个过程中获得的专业知识 该奖项将使达文波特博士能够获得未来的R01资金，并过渡到独立的研究生涯 重点关注新生儿PLT生物学，特别是PLT与新生儿肺的相互作用。

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.