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: 10402766
• 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/10402766
• 关键词: 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; 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; Immune; Immune system; Immunology; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-17; Interleukin-6; Knowledge; Laboratories; Link; Lung; Lung diseases; 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; Plant Roots; Plasma; Platelet Count measurement; Platelet Transfusion; Premature Infant; Process; Publishing; Pulmonary Inflammation; Randomized; Research; Research Design; Research Personnel; Research Training; 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; base; career; career development; clinical practice; clinically relevant; cytokine; design; experimental study; high risk; improved; improved outcome; insight; lung injury; macrophage; medical schools; meetings; mortality; mortality risk; mouse model; neonatal human; neonatal infection; neonatal mice; neonatal morbidity; neonatal sepsis; neonate; neutrophil; polymicrobial sepsis; premature; preterm newborn; prevent; primary outcome; pulmonary function; randomized trial; response; secondary outcome; statistics; success; 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 (Patricia Davenport) 博士是一位新生儿血液学独立学术研究员。 在临床相关和研究不足的领域工作的富有成效和敬业的年轻医师科学家。 是止血和炎症的积极参与者，但临床对这双重作用的认识却滞后 研究发现背后的原因，特别是早产儿自发性出血的风险很高。 （特别是颅内），因此通常以比儿童或成人更高的 PLT 计数进行输血。 然而，最近一项针对早产儿的大型随机试验发现，自由派 PLT 输注会增加死亡率和慢性肺部疾病的风险，但不会减少出血。 介导这些发现的机制尚不清楚，但我们勇敢地说它们至少部分与 新生儿和成人 PLT 之间的发育差异 该提案的首要目标是 通过更好地了解新生儿血小板减少症的后果来改善新生儿血小板减少症的管理 我们的总体假设是，PLT 输血对患有各种潜在病症的新生儿的影响。 PLT 输血增加新生儿死亡率和慢性肺病的严重程度是由 为了检验这一假设，我们设计了以下具体方案。 目的： 1. 确定 PLT 输注对患有或不患有内毒素血症的新生小鼠的影响； 2. 确定 PLT 输注对脓毒症新生儿模型死亡率的影响；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具有非常重要的意义。 从中获得的经验将为临床实践和研究提供信息，达文波特博士将接受她的同事的指导。 导师：Martha Sola-Visner 博士（美国国立卫生研究院资助的新生儿 PLT 生物学领域研究员）和 Stella 博士 Kourembanas 是一位世界著名的新生儿肺生理学和慢性肺病研究者。 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 具有输血医学和免疫学、新生儿败血症和炎症、传染病专业知识的科学家 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）和哈佛医学院为候选人的职业发展提供了理想的环境。 BCH 新生儿医学部门致力于帮助 Davenport 博士取得成功，并已保证至少 75% 受保护的时间致力于本提案中描述的活动 详细的职业发展和培训。 提出计划，包括指导研究、教学课程、研讨会和科学演讲 会议，以及稿件撰写和 R00 提交计划。从中获得的专业知识和知识。 该奖项将使 Davenport 博士能够获得未来的 R01 资助并过渡到独立研究生涯 专注于新生儿 PLT 生物学，特别是 PLT 与新生儿肺的相互作用。