Genetic Analysis of Hyperoxia Induced Acute Lung Injury

高氧所致急性肺损伤的基因分析

• 批准号: 7624521
• 负责人: Daniel R Prows
• 金额: $ 37.81万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624521
• 关键词: 129X1/SvJ Mouse; Acute; Acute Lung Injury; Address; Adult; Adult Respiratory Distress Syndrome; Aerosols; Affect; Alleles; Animals; Backcrossings; Candidate Disease Gene; Cessation of life; Clinical Research; Complex; Computer Simulation; Congenic Strain; Critical Illness; End Point; Epigenetic Process; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Goals; Human; Hyperoxia; In Vitro; Individual; Inheritance Patterns; Knowledge; Link; Maps; Modeling; Monitor; Mus; Myocardial Infarction; Names; Newborn Respiratory Distress Syndrome; Nickel; Other Genetics; Outcome; Ozone; Parents; Patients; Penetrance; Physical Map of the Human Genome; Population; Predisposition; Premature Infant; Quantitative Trait Loci; Rate; Recombinants; Research Personnel; Resistance; Respiratory distress; Role; Sample Size; Severities; Staging; Susceptibility Gene; Testing; Time; base; congenic; gene interaction; genetic analysis; improved; in vivo; lung injury; mortality; mouse model; novel; physical mapping; prototype; segregation; sex; trait

Acute lung injury (ALI) and its most severe presentation acute respiratory distress syndrome (ARDS), represent a full spectrum of a complex and devastating illness, with associated mortality hovering at 30¿ 40%. Even supplemental O2, a routine and needed therapy for such patients, paradoxically causes lung injury. In fact, the detrimental effects of O2 have established hyperoxic acute lung injury (HALI) as a prototype to study respiratory distress syndromes in experimental animals. To confront the high ALI mortality much differently than current candidate gene studies, we have established a mouse model (sensitive C57BL/6J and resistant 129X1/SvJ mice) to assess the genetic complexity of HALI, with a longterm goal to identify genes affecting strain survival differences. Segregation analysis of 840 F2 mice generated from the four possible intercrosses between these strains verified that survival time is a complex trait with decreased penetrance, and significant sex, cross, and parent-of-origin effects. Quantitative trait locus (QTL) analyses of the 840 F2 mice identified three highly significant loci (named Shali1¿3, for Survival to hyperoxic acute lung injury) and one significant locus (Shali4) in the total F2 population. Pairwise analysis identified several additive gene-gene interactions amongst the QTLs and an epistatic interaction with an otherwise unlinked locus. Segregation and QTL analyses demonstrated that resistance alleles originate from both parental strains and recombine to determine individual HALI susceptibility. These results have led to the following hypothesis: Shali QTLs contain susceptibility genes that, when grouped together in appropriate allelic combinations, will significantly affect HALI survival time. The primary objective of this application is to set the stage for physical mapping and quantitative trait gene identification, with a major focus on Shali1. To accomplish this, we propose three Specific Aims: 1) confirm QTL results in vivo by constructing reciprocal congenic strains for the 4 Shali QTLs significantly linked to HALI survival time in the B¿S model; establish which QTL(s) significantly contribute to HALI survival time; 2) test candidate genes and reduce the Shali1 QTL interval to a level amenable to physical mapping; prioritize and critically assess positional candidate genes for functional significance; concurrently reduce the Shali1 QTL interval by constructing and testing congenic sub-strains; and 3) determine the best allelic combinations for increased and decreased survival in multi-congenic strains containing the corresponding QTLs in the appropriate strain; generate reciprocal congenics with all 4 sensitive or all 4 resistant Shali alleles in the same strain. Mouse lines derived from these studies will provide impetus and focus towards identifying key genes affecting HALI survival.

急性肺损伤（ALI）及其最严重的急性呼吸遇险综合征（ARDS）， 代表了一个复杂而毁灭性疾病的全部范围，相关的死亡率徘徊在30？ 40％。即使是补充O2，这是此类患者的常规和需要治疗，也会引起肺 实际上，O2的有害作用已确立了高氧化急性肺损伤（HALI） 研究实验动物中呼吸窘迫综合征的原型。面对高级阿里 与当前候选基因研究的死亡率不同，我们已经建立了小鼠模型 （敏感的C57BL/6J和抗性129x1/SVJ小鼠）长期评估HALI的遗传复杂性 识别影响应变存活差异的基因的目标。 840 F2小鼠的隔离分析 从这些菌株之间的四个可能的间交叉中产生的生存时间是一个复杂的 具有改善的外观，重大的性，交叉和父母的特征。定量性状 840 F2小鼠的基因座（QTL）分析确定了三个高度显着的基因座（命名为Shali1¿3，用于生存 在F2总体中，高氧化急性肺损伤）和一个显着的基因座（Shali4）。成对 分析确定了QTL之间的其他几种基因 - 基因相互作用和上皮相互作用 带有一个原本未链接的基因座。隔离和QTL分析表明，电阻等位基因 源自父母菌株和重组，以确定单个哈利的敏感性。这些 结果导致了以下假设：shali qtls包含易感基因，当 以适当的shillig组合组合在一起，将显着影响哈利的生存时间。 该应用的主要目的是为物理映射和定量性状基因设定阶段 识别，主要关注Shali1。为此，我们提出了三个具体目标：1）确认 QTL通过为4个shali QTL构建相互构造的互惠先天性菌株而导致体内产生体内。 B？S模型中的Hali生存时间；确定哪些QTL显着促进了哈利生存时间； 2）测试候选基因并将SHALI1 QTL间隔降低到适合物理映射的水平； 优先和关键评估位置候选基因的功能意义；同时减少 SHALI1 QTL间隔通过构建和测试先天性亚汇率； 3）确定最佳的shilic 组合含有相应的多共产菌株中生存率增加和降低 QTL在适当的应变中；具有所有4个敏感或全部4个抗性Shali 等位基因处于相同的菌株中。从这些研究得出的小鼠线将提供动力，并专注于 识别影响哈利生存的关键基因。