Mechanisms of Fetal Membrane Rupture

胎膜破裂的机制

• 批准号: 7863904
• 负责人: JEROME F STRAUSS
• 金额: $ 1.18万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863904
• 关键词: Adverse effects; Affect; African American; Alleles; Attention; Biochemical; Candidate Disease Gene; Clinical; Collagen; CpG Islands; DNA Methylation; Data; Dose; Elastin; Epigenetic Process; Fetal Membranes; Fibrillar Collagen; Fibroblasts; Gene Expression; Gene Family; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Heritability; Individual; Interstitial Collagenase; Investigation; Laboratory Research; Matrix Metalloproteinases; Membrane; Methylation; Molecular; Molecular Chaperones; Morbidity - disease rate; Pattern; Post-Translational Protein Processing; Premature Birth; Premature Rupture Fetal Membranes; Protein-Lysine 6-Oxidase; Proteins; Risk; Rupture; Testing; Twin Multiple Birth; Variant; Woman; amnion; base; crosslink; gene synthesis; genetic variant; novel strategies; preterm premature rupture of membranes; promoter; racial and ethnic disparities

DESCRIPTION (provided by applicant): Preterm premature rupture of the fetal membranes (PPROM) is a major cause of maternal morbidity and premature birth. Studies conducted during the current period of support revealed that polymorphisms in genes encoding matrix metalloproteinases (MMPs) contribute to risk of unscheduled membrane rupture. We now propose to 1) determine whether variants in genes encoding proteins involved in collagen synthesis and posttranslational modification, including the SERPINH1 gene, which encodes a chaperone that regulates collagen synthesis, and the lysyl oxidase (LOX) gene family which catalyze collagen cross- linking, confer risk of PPROM. The hypotheses to be tested are that: 1) the 656 T allele of the SERPINH1 gene is an ethnic-selective factor contributing to preterm birth in African-Americans; 2) a 12 bp deletion adjacent to the 656 T SNP opposes the adverse effect of the 656 T allele on PPROM; 3) the 12 bp deletion increases SERPINH1 promoter activity mitigating the effect of the 656 T allele; 4) collagen synthesis is reduced in amnion fibroblasts carrying the 656 T allele, but not the 656 T allele in the presence of the 12 bp deletion; 5) the fibrillar collagen content of the amnion is reduced in carriers of the 656 T allele, but not when the 12 bp deletion is present; 6) the 656 T allele dose is correlated with amnion fibroblast collagen synthesis and amnion collagen content, as well as risk of PPROM; 7) that functional polymorphisms exist in the LOX gene family that result in altered gene expression or enzymatic activity and are associated with risk of PPROM; and 8) that these variants affect amnion collagen cross-linking. Based on preliminary data, attention will be focused on the LOXL1 gene. A twin-based study of the genetics of preterm birth will be incorporated as a new approach to establish heritability and gene finding. 2) determine if epigenetic factors contribute to expression of PPROM candidate genes. The hypotheses to be tested are: 1) that variation in methylation of CpG islands in the promoters of MMP and collagen synthesis genes regulate gene expression; 2) that certain metyhylation marks result in allele-specific transcription; 3) that methylation status of amnion PPROM candidate genes varies among individuals; 4) that methylation patterns of these genes that influence transcription are associated with risk of PPROM; 5) that epigenetic marks modify the impact of genetic variation. This hypothesis will be tested using the MMP1 promoter 930 T/C SNP as an exemplar. The proposed studies represent a synthesis of clinical and laboratory research that will encompass molecular and biochemical analyses that relate to the genetic variants under investigation. These studies will disclose genetic and epigenetic factors that contribute to PPROM including racial/ethnic disparity in preterm birth, allow the identification of women at risk of PPROM, and identify genetic markers predicting PPROM.Preterm premature rupture of the fetal membranes (PPROM) is a major cause of maternal morbidity and premature birth. The proposed studies will determine whether variants or epigenetic factors in genes encoding proteins involved in collagen synthesis confer risk of PPROM.

描述（由申请人提供）：早产胎膜早破（PPROM）是孕产妇发病和早产的主要原因。在当前支持期间进行的研究表明，编码基质金属蛋白酶（MMPs）的基因多态性与非计划性膜破裂的风险有关。我们现在建议1)确定编码胶原合成和翻译后修饰蛋白的基因变异，包括编码调节胶原合成的伴侣蛋白的SERPINH1基因，以及催化胶原交联的赖氨酸氧化酶（LOX）基因家族，是否会导致PPROM的风险。需要验证的假设是：1)SERPINH1基因的656 T等位基因是导致非裔美国人早产的种族选择因素；2) 656 T SNP附近的12bp缺失与656 T等位基因对PPROM的不利影响相反；3) 12bp的缺失增加了SERPINH1启动子活性，减轻了656 T等位基因的影响；4)在携带656 T等位基因的羊膜成纤维细胞中，胶原合成减少，而在656 T等位基因缺失的情况下，胶原合成不减少；5)携带656 T等位基因的羊膜纤维胶原含量减少，但当存在12 bp缺失时则不减少；6) 656 T等位基因剂量与羊膜成纤维细胞胶原合成、羊膜胶原含量及PPROM发生风险相关；7) LOX基因家族存在功能多态性，导致基因表达或酶活性改变，与PPROM风险相关；8)这些变异影响羊膜胶原交联。在初步数据的基础上，将重点关注LOXL1基因。以双胞胎为基础的早产遗传学研究将被纳入建立遗传力和基因发现的新方法。2)确定表观遗传因素是否影响PPROM候选基因的表达。拟验证的假设为：1)MMP和胶原合成基因启动子中CpG岛甲基化的变化调节基因表达；2)某些甲基化标记导致等位基因特异性转录；3)羊膜PPROM候选基因的甲基化状态在个体间存在差异；4)这些影响转录的基因的甲基化模式与PPROM的风险相关；5)表观遗传标记改变了遗传变异的影响。这一假设将以MMP1启动子930 T/C SNP为例进行验证。拟议的研究是临床和实验室研究的综合，将包括与所调查的遗传变异有关的分子和生化分析。这些研究将揭示导致PPROM的遗传和表观遗传因素，包括早产中的种族/民族差异，允许识别有PPROM风险的妇女，并确定预测PPROM的遗传标记。早产胎膜早破（PPROM）是产妇发病和早产的主要原因。拟议的研究将确定是否变异或表观遗传因素的基因编码蛋白参与胶原合成增加PPROM的风险。