Genetic Polymorphisms in Pediatric Lung Injury

描述（由申请人提供）：本申请的目的是进一步了解社区获得性肺炎（CAP）患儿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，从轻微肺损伤到严重呼吸衰竭和急性呼吸窘迫综合征（ARDS），在一定程度上代表了促炎/促纤维化和抗炎/抗纤维化介质之间的不平衡，这种不平衡部分受到遗传决定因素的影响。对该提案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引起的儿童肺损伤和呼吸衰竭的临床表现或结果相关。该项目将寻找遗传标记（snp）的证据，这些证据可用于预测CAP患儿的预后不良风险，并可能从早期或更积极的干预中受益。从该项目获得的试点数据将用于规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，本建议的具体目的如下：验证与炎症有关的基因中已知的单核苷酸多态性（snp）的预测，特别是tnf - α、IL-8、ICAM-1、Fas和ACE，与cap诱导的儿童严重肺损伤和呼吸衰竭有关。验证tnf - α和/或Fas基因位点的特定SNP单倍型与cap诱导的儿童严重肺损伤和呼吸衰竭相关的预测。本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遗传多态性的频率。研究团队将包括在儿科重症监护、传染病、分子科学和流行病学方面受过训练的研究人员。该提案的优势包括可以接触到大量的CAP儿童，研究人员在多态性分析方面的记录，特别是在CAP患者中，以及参与机构承诺为研究人员提供最先进的技术。

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.