Genetic Polymorphisms in Pediatric Lung Injury

描述（由申请人提供）：本提案的目的是进一步了解社区获得性肺炎（CAP）儿童急性呼吸衰竭的发病机制。中心假设是CAP诱导的肺损伤的连续性，从最小肺损伤到严重呼吸衰竭和急性呼吸窘迫综合征（ARDS），部分代表促炎/促纤维化和抗炎/抗纤维化介质之间的不平衡，并且这种不平衡部分受遗传决定因素的影响。对这一建议的支持将用于检查和分析试点数据，以确定特定的遗传多态性是否与CAP诱导的肺损伤和呼吸衰竭儿童的临床表现或结局相关。该项目将寻求遗传标记（SNPs）的证据，可用于预测CAP儿童，这些儿童具有不良结局的高风险，并可能从早期或更积极的干预中受益。从该项目中获得的试验数据将用于计划一项更大的前瞻性多机构队列研究。为了验证我们的假设，该提案的具体目的如下：验证以下预测：涉及炎症的基因中已知的单核苷酸多态性（SNP），特别是TNF-alpha、IL-8、ICAM-1、Fas和ACE，与CAP相关。儿童严重肺损伤和呼吸衰竭。验证TNF-α和/或Fas基因位点的特定SNP单倍型与CAP诱导的儿童重度肺损伤和呼吸衰竭相关的预测。该提案将利用多学科方法分析和比较不同程度CAP诱导的肺损伤和呼吸衰竭儿童中特定基因多态性的频率。该研究小组将包括接受过儿科重症监护、传染病、分子科学和流行病学培训的研究人员。该提案的优势包括获得大量CAP儿童人群，研究者在多态性分析方面的跟踪记录，特别是在CAP患者中，以及参与机构向研究者提供最先进技术的承诺。

DESCRIPTION (provided by applicant): The objective of this proposal is to further understand the pathogenesis of acute respiratory failure in children with community-acquired pneumonia (CAP). The central hypothesis is that the continuum of CAP-induced lung injury, from minimal lung injury to severe respiratory failure and acute respiratory distress syndrome (ARDS), represents, in part, an imbalance between pro-inflammatory/pro-fibrotic and anti-inflammatory/antifibrotic mediators, and that this imbalance is in part influenced by genetic determinants. Support for this proposal will be used to examine and analyze pilot data in order to determine if specific genetic polymorphisms are associated with the clinical presentation of, or outcome from, CAP-induced lung injury and respiratory failure in children. The project will seek evidence of genetic markers (SNPs) that can be utilized to predict children with CAP that are at high risk for poor outcomes and may benefit from earlier or more aggressive intervention. The pilot data obtained from this project will be used to plan for a study of a larger prospective, multi-institutional cohort. To test our hypothesis, the specific aims of this proposal are as follows: To test the prediction that known single nucleotide polymorphisms (SNPs) in genes involving inflammation, specifically TNF-alpha, IL-8, ICAM-1, Fas, and ACE, are associated with CAP-induced severe lung injury and respiratory failure in children. To test the prediction that specific SNP haplotypes in the TNF-alpha and/or Fas gene loci are associated with CAP-induced severe lung injury and respiratory failure in children. This proposal will utilize a multi-disciplinary approach to analyze and compare frequencies of specific genetic polymorphisms in children with varying degrees of CAP-induced lung injury and respiratory failure. The research team will include investigators trained in Pediatric Critical Care, Infectious Diseases, Molecular Sciences, and Epidemiology. The strengths of this proposal include access to large populations of children with CAP, the track record of the investigators in polymorphic analysis, particularly in patients with CAP, and the commitment of the participating institution to provide state-of-the-art technologies to the investigators.