2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655714摘要：極低出生體重早產兒之死亡率，近年來已顯著降低，但極度早產兒仍飽受慢性疾病的威脅。氧氣與呼吸器治療會使早產兒產生體內反應，包括發炎，蛋白酵素與生長因子異常，肺部組織發育不良與纖維化，導致慢性肺疾。雖然關於新生兒氧化壓力性疾病的探討，包括基因多型性、發炎誘發物質、氧化壓力產物的偵測等，已有部份報告，然而對於致病機轉了解非常有限。令人感興趣的是早產兒慢性肺疾的發生率在國內外醫學中心間存在相當差異，我們判斷與早產兒的體質及出生後的環境暴露有關。本研究主要藉由探討早產兒全基因體甲基化與相關基因的表現，進一步了解早產與環境因素對於氧化壓力性疾病的外遺傳機制影響。透過跨科際的團隊研究，經由探討全基因的甲基化我們針對新生兒高黃疸與體重過輕或過重兒諸如Russell-Silver與Beckwith-Wiedemann症候群，已有初步成果。加上文獻顯示有些肺部發育不良歸咎於活性氧化物與基因的甲基化異常，因此對新生兒氧化壓力性疾病，試著進行研究並期待提供臨床上預測生物指標與合適之治療方針，避免氧化壓力性疾病的產生。第一年:初步收集極低出生體重的早產兒，分別針對典型的數例慢性肺疾病個案，比較新生兒慢性肺疾病個案與對照組之全基因體去氧核醣核酸甲基化變異的差異;第二年:將有系統地收集極低出生體重早產兒慢性肺疾病個案，比較其發病前後全基因體的甲基化差異與特殊基因表現變化相關之分子實驗分析，並開發潛在性外遺傳預測生物指標;第三年:將探討早產兒氧化壓力相關疾病之全基因體外遺傳機制變化，並藉由小鼠動物模型，分析高氧傷害對於全基因去氧核醣核酸甲基化程度的影響，並找出相關基因序列,進而探討特定基因甲基化在氧氣誘發慢性肺疾病病變所扮演之角色。<br> Abstract: Background and study purposesThe mortality rate of preterm infants with very low birth weight (VLBW, birth weight<1,500 grams) has significantly decreased during recent decades. However, the morbidityrates of neonatal diseases remain unchanged among these small preterm infants as featured bythe high incidence of oxidative stress diseases such as chronic lung disease (CLD) (alsoknown as bronchopulmonary dysplasia, BPD). Despite recent exploration in the field of genepolymorphism, inflammatory mediators, and oxidative products detection, the mechanismsunderlying the oxidative stress diseases among VLBW infants remain unclear. Supplementaloxygen in premature infants contributes to the development of CLD is characterized bydysregulated inflammation and altered expression of proteases and growth factors. In additionto these changes, oxygen also induces aberrant physiologic responses includingvasoconstriction, vasodilatation, and neovascularization that can be damaging in prematurelungs. These can result in pulmonary fibrosis, asymmetrical aeration, and respiratoryinsufficiency. Interestingly, the incidence of CLD in VLBW infants is quite variable amongdifferent medical centers worldwide. We suspect that the variable incidence is probably basedon the genetic and epigenetic factors among these VLBW infants due to the uniqueness ofpreterm neonates and the environmental impacts after their birth.Epigenetics refer to all meiotically and mitotically heritable changes in phenotype or ingene expression states that are not coded in the DNA sequence itself. Epigenome mechanismsselectively activate or inactivate genes that control cell growth, proliferation and apoptosisand determine when and where a gene is expressed during development. Alterations ofepigenetic patterns are one mechanism by which prenatal exposures affect disease risk later inlife. Furthermore, the early appearance of epigenetic changes may give an advantage fortimely detection of oxygen induced pulmonary injury and related neonatal morbid conditions.From the microRNA detection study and the whole-genome DNA methylation approach,we had found some preliminary results in exploring the genetic mechanisms related to BPD;and the epigenetic mechanisms on the pathogenesis of neonatal hyperbilirubinemia, small forgestational age, large for gestational age infants especially in infants with Russell-Silversyndrome or Beckwith-Wiedemann syndrome. This study aims to explore the whole-genomeepigenetic alteration mechanisms and genetic modifications of neonatal oxidative stressdiseases especially for CLD in VLBW infants. Increasing knowledge of the mechanismsunderlying oxygen toxicity may be used to explore preventive strategies in minimizing tissueinjury and optimizing long-term morbidities in VLBW infants.Framework of projectFirst year: To preliminarily explore the whole-genome DNA methylation profiles among12 VLBW infants with and without CLD.Second year: Systemically recruit VLBW infants with or without CLD and perform thefunctional exploration of potential genes and to analyze the DNA methylation alterations inthe blood samples collected at different timing including the days immediately after birth andat days of diagnosis. Identify markers in the epigenomics to predict premature infants at riskof CLD.Third year: Further investigation concerning the epigenetic mechanisms of neonataloxidative stress diseases in addition to CLD; and set up the hyperoxic lung injury mice modelfor evaluation of the genome-wide DNA methylation changes underlying oxidative stress andexploration of the possible associated molecular mechanism of developing CLD in mice. Expected resultsThe theme of this study is to explore the developmental origin and environmentalimpacts on neonatal oxidative stress diseases based on genetic and epigenetic perspective andto provide important information regarding preventive and therapeutic management.