Genetic variation and biomarkers in children with acute lung injury

急性肺损伤儿童的遗传变异和生物标志物

• 批准号: 8676047
• 负责人: Mary K Dahmer
• 金额: $ 32.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676047
• 关键词: Genetic; variation; biomarkers; children; acute

DESCRIPTION (provided by applicant): Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long- term morbidity and the high mortality (estimated at 20-50%) associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. There have been no large, well-powered studies examining whether specific genetic variants or plasma biomarkers in children with lung injury are associated with the increased likelihood of progressing to ALI/ARDS. This proposal is an ancillary study to a large, multi-institutional clinical trial enrolling approximately 2800 intubated children with parenchymal lung disease. The study described in this proposal will compare genetic variations in specific candidate genes and plasma biomarkers in those children who develop ALI/ARDS with those who do not develop ALI/ARDS within the cohort of the parent study. This cohort of at risk children is much larger than any that has been studied to date. Our hypothesis is that intubated children with parenchymal lung disease who develop ALI/ARDS will have different frequencies of specific genetic variants in candidate genes and altered levels of plasma biomarkers corresponding to these genes compared with those intubated children who do not develop ALI/ARDS. These unique comparisons in this large cohort of intubated children will include an analysis of: 1) genetic variations in selected candidate genes involved in inflammation, coagulation and surfactant synthesis and 2) selected plasma biomarkers of inflammation, coagulation and surfactant. The primary outcome measure for this ancillary proposal is the development of ALI/ARDS. Another unique aspect of this proposal is that the cohort will be stratified into Caucasian and African American subgroups for analyses. If children at greater risk for ALI/ARDS can be identified using the findings from this study, future studies would be designed to determine whether the information could be used for early identification of pediatric patients at high risk for development of ALI/ARDS thereby allowing earlier initiation of specific lung protective strategies leading to lower mortality, fewer days of mechanical ventilation, shorter intensive care and hospital length of stay, and lower hospital costs. In addition, results from this proposal will provide further insight into the pathophysiology of ALI/ARDS in children. PUBLIC HEALTH RELEVANCE: Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long-term morbidity and the high mortality associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. However, the response to these clinical conditions is variable between different individuals with some children recovering without complications while others go on to develop ALI/ARDS. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. This proposal will examine whether an individual's genetic make-up might influence the development of ALI/ARDS in children and/or whether specific plasma biomarkers may help identify those children who will progress to develop severe lung injury. Identifying genetic variants and biomarkers that influence the severity of lung injury or predict which children will progress to more severe lung injury may help better understand the pathophysiology of ALI/ARDS, help identify children who may be at greater risk for the development of ALI/ARDS, and perhaps identify novel therapeutic targets. (End of Abstract)

描述（由申请人提供）： 识别出发生急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 的风险最大的儿童对于开始早期治疗并限制与这些疾病相关的急性和长期发病率以及高死亡率（估计为 20-50%）至关重要。 ALI/ARDS 发生于患有特定临床病症的儿童，包括肺炎、误吸或脓毒症。不幸的是，在这个高危人群中识别最有可能罹患 ALI/ARDS 的儿童非常困难。目前还没有大型、有力的研究来检验肺损伤儿童的特定基因变异或血浆生物标志物是否与进展为 ALI/ARDS 的可能性增加有关。该提案是一项大型、多机构临床试验的辅助研究，该试验招募了约 2800 名患有实质肺病的插管儿童。本提案中描述的研究将比较母研究队列中发生 ALI/ARDS 的儿童与未发生 ALI/ARDS 的儿童的特定候选基因和血浆生物标志物的遗传变异。这批高危儿童的数量比迄今为止所研究的任何儿童都要大。我们的假设是，与未发生 ALI/ARDS 的插管儿童相比，发生 ALI/ARDS 的患有实质肺疾病的插管儿童的候选基因中特定遗传变异的频率不同，并且与这些基因相对应的血浆生物标志物水平发生改变。在这一大群插管儿童中进行的独特比较将包括分析：1）涉及炎症、凝血和表面活性剂合成的选定候选基因的遗传变异；2）选定的炎症、凝血和表面活性剂血浆生物标志物。该辅助提案的主要成果指标是 ALI/ARDS 的发展。该提案的另一个独特之处是，该群体将被分为白人和非裔美国人亚组进行分析。如果可以利用本研究的结果识别出患有 ALI/ARDS 风险较高的儿童，那么未来的研究将旨在确定这些信息是否可用于早期识别发生 ALI/ARDS 高风险的儿科患者，从而可以更早地启动特定的肺保护策略，从而降低死亡率、减少机械通气天数、缩短重症监护和住院时间以及降低医院费用。此外，该提案的结果将进一步深入了解儿童 ALI/ARDS 的病理生理学。公众健康相关性：识别发生急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 的风险最大的儿童对于开始早期治疗以及限制与这些疾病相关的急性和长期发病率以及高死亡率至关重要。 ALI/ARDS 发生于患有特定临床病症的儿童，包括肺炎、误吸或脓毒症。然而，不同个体对这些临床状况的反应各不相同，一些儿童康复后没有并发症，而另一些儿童则继续发展为 ALI/ARDS。不幸的是，在这个高危人群中识别最有可能罹患 ALI/ARDS 的儿童非常困难。该提案将检查个体的基因组成是否可能影响儿童 ALI/ARDS 的发展和/或特定血浆生物标志物是否可以帮助识别那些将发展为严重肺损伤的儿童。识别影响肺损伤严重程度的基因变异和生物标志物，或预测哪些儿童将发展为更严重的肺损伤，可能有助于更好地了解 ALI/ARDS 的病理生理学，帮助识别可能发生 ALI/ARDS 的风险更大的儿童，并可能确定新的治疗靶点。 （摘要完）

项目成果

A Targeted Analysis of Serial Cytokine Measures and Nonpulmonary Organ System Failure in Children With Acute Respiratory Failure: Individual Measures and Trajectories Over Time.

急性呼吸衰竭儿童的系列细胞因子测量和非肺器官系统衰竭的针对性分析：个体测量和随时间变化的轨迹。

• DOI: 10.1097/pcc.0000000000003286
• 发表时间: 2023
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Ardila,SilviaM;Weeks,HeidiM;Dahmer,MaryK;Kaciroti,Niko;Quasney,Michael;Sapru,Anil;Curley,MarthaAQ;Flori,HeidiR;BiomarkersinChildrenwithAcuteLungInjury(BALI)andRandomizedEvaluationforSedationTitrationforRespiratoryFail
• 通讯作者: BiomarkersinChildrenwithAcuteLungInjury(BALI)andRandomizedEvaluationforSedationTitrationforRespiratoryFail