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: 8252154
• 负责人: Mary K Dahmer
• 金额: $ 5.2万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252154
• 关键词: Acute; Acute Lung Injury; Admission activity; Adult; Adult Respiratory Distress Syndrome; African American; Ancillary Study; Aspiration Pneumonia; Biological Markers; Candidate Disease Gene; Child; Childhood; Clinical; Coagulation Process; Critically ill children; Development; Diagnosis; Early identification; Early treatment; Enrollment; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Markers; Genetic Variation; Health; Hospital Costs; Individual; Inflammation; Intensive Care; Length of Stay; Lung; Lung diseases; Mechanical ventilation; Mediator of activation protein; Morbidity - disease rate; Multi-Institutional Clinical Trial; Outcome Measure; Parents; Patients; Pediatric Intensive Care Units; Plasma; Population; Populations at Risk; Process; Proteins; Regulation; Research Proposals; Risk; Sepsis; Severities; Subgroup; Testing; Variant; abstracting; caucasian American; cohort; design; genetic variant; high risk; insight; lung injury; mortality; new therapeutic target; primary outcome; response; surfactant

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）： 识别具有发生急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的最大风险的儿童对于开始早期治疗和限制与这些病症相关的急性和长期发病率以及高死亡率（估计为20-50%）是至关重要的。ALI/ARDS发生于具有特定临床病症的儿童，包括肺炎、吸入性或败血症。不幸的是，很难在这个高危人群中识别出最有可能发生ALI/ARDS的儿童。目前还没有大型的、有充分把握的研究来检查肺损伤儿童的特定遗传变异或血浆生物标志物是否与进展为ALI/ARDS的可能性增加相关。该提案是一项大型多机构临床试验的辅助研究，该试验入组了约2800例患有实质性肺病的插管儿童。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的儿童中特定候选基因和血浆生物标志物的遗传变异。这群高危儿童比迄今为止研究的任何儿童都要大得多。我们的假设是，与未发生ALI/ARDS的插管儿童相比，发生ALI/ARDS的实质性肺病插管儿童在候选基因中具有不同频率的特定遗传变异以及与这些基因对应的血浆生物标志物水平的改变。在这一大型插管儿童队列中的这些独特比较将包括分析：1）选定的参与炎症、凝血和表面活性剂合成的候选基因的遗传变异和2）选定的炎症、凝血和表面活性剂的血浆生物标志物。该辅助方案的主要结局指标是ALI/ARDS的发生。该提案的另一个独特之处在于，将队列分层为高加索人和非洲裔美国人亚组进行分析。如果使用本研究的结果可以识别出具有更高ALI/ARDS风险的儿童，则未来的研究将旨在确定这些信息是否可以用于早期识别具有发生ALI/ARDS高风险的儿科患者，从而允许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，降低医院成本。此外，本研究的结果将为进一步了解儿童ALI/ARDS的病理生理学提供依据。公共卫生相关性：确定儿童谁有最大的风险发展为急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是至关重要的开始早期治疗和限制急性和长期发病率和高死亡率与这些条件。ALI/ARDS发生于具有特定临床病症的儿童，包括肺炎、吸入性或败血症。然而，对这些临床状况的反应在不同的个体之间是可变的，一些儿童在没有并发症的情况下恢复，而另一些儿童则继续发展ALI/ARDS。不幸的是，很难在这个高危人群中识别出最有可能发生ALI/ARDS的儿童。该提案将研究个体的遗传组成是否可能影响儿童ALI/ARDS的发展和/或特定的血浆生物标志物是否可能有助于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或预测哪些儿童将发展为更严重的肺损伤的遗传变异和生物标志物可能有助于更好地理解ALI/ARDS的病理生理学，有助于识别可能处于更大的ALI/ARDS发展风险的儿童，并可能识别新的治疗靶点。(End摘要）