Mechanisms of Fetal Membrane Rupture

胎膜破裂的机制

• 批准号: 8055258
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055258
• 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

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) To 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 crosslinking, 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) To 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.

早产胎膜早破（PPROM）是孕产妇发病的主要原因， 早产在本支助期内进行的研究表明，基因多态性 编码基质金属蛋白酶（MMPs）的蛋白质增加了非计划性膜破裂的风险。我们现在 建议1）确定编码参与胶原合成的蛋白质的基因中的变体 和翻译后修饰，包括SERPINH 1基因，它编码一种伴侣蛋白， 调节胶原合成，赖氨酰氧化酶（LOX）基因家族催化胶原交联， 有PPROM的风险。待检验的假设是：1）SERPINH 1的<$656 T等位基因 基因是导致非裔美国人早产的种族选择性因素; 2）12 bp缺失 与<$656 T SNP相邻的12 bp缺失可对抗<$656 T等位基因对PPROM的不利影响; 增加SERPINH 1启动子活性，减轻<$656 T等位基因的影响; 4）胶原蛋白合成， 在携带<$656 T等位基因的羊膜成纤维细胞中减少，但在12 bp的 缺失; 5）在<$656 T等位基因的携带者中，羊膜的纤维胶原含量减少，但当 存在12 bp缺失; 6）± 656 T等位基因剂量与羊水成纤维细胞胶原蛋白合成相关 和羊膜胶原含量，以及PPROM的风险; 7）LOX存在功能多态性， 导致基因表达或酶活性改变并与PPROM风险相关的基因家族; 和8）这些变体影响羊膜胶原交联。根据初步数据， 关注LOXL 1基因。一项以双胞胎为基础的早产遗传学研究将作为一项新的 建立遗传力和基因发现的方法。2)为了确定表观遗传因素是否有助于 PPROM候选基因的表达。待检验的假设是：1）甲基化的变化 MMP和胶原合成基因启动子中的CpG岛调节基因表达; 2）某些 甲基化标记导致等位基因特异性转录; 3）羊膜PPROM甲基化状态 候选基因在个体之间存在差异; 4）这些基因的甲基化模式影响 转录与PPROM的风险有关; 5）表观遗传标记改变了遗传标记的影响， 变化量将使用MMP 1启动子<$930 T/C SNP作为范例来检验该假设。的 拟议的研究代表了临床和实验室研究的综合， 与研究中的遗传变异相关的生化分析。 这些研究将揭示导致PPROM的遗传和表观遗传因素，包括种族/民族 早产的差异，允许识别有PPROM风险的妇女，并确定遗传标记 预测PPROM。

项目成果

A single nucleotide polymorphism in the promoter of the LOXL1 gene and its relationship to pelvic organ prolapse and preterm premature rupture of membranes.

• DOI: 10.1177/1933719108330567
• 发表时间: 2009-05
• 期刊: Reproductive sciences (Thousand Oaks, Calif.)
• 作者: Ferrell G;Lu M;Stoddard P;Sammel MD;Romero R;Strauss JF 3rd;Matthews CA
• 通讯作者: Matthews CA

Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes.

• DOI: 10.1093/hmg/ddm381
• 发表时间: 2008-04
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Hongyan Wang;Masaki Ogawa;J. Wood;M. Bartolomei;M. Sammel;J. Kusanovic;S. Walsh;R. Romero;J. Strauss

Estimating fetal and maternal genetic contributions to premature birth from multiparous pregnancy histories of twins using MCMC and maximum-likelihood approaches.

• DOI: 10.1375/twin.12.4.333
• 发表时间: 2009-08
• 期刊: Twin research and human genetics : the official journal of the International Society for Twin Studies
• 作者: York TP;Strauss JF 3rd;Neale MC;Eaves LJ
• 通讯作者: Eaves LJ

Induction of matrix metalloproteinases and collagenolysis in chick embryonic membranes before hatching.

• DOI: 10.1095/biolreprod60.1.183
• 发表时间: 1999
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: H. Lei;E. Furth;R. Kalluri;P. Wakenell;C. Kallen;J. Jeffrey;P. Leboy;J. Strauss

Racial differences in genetic and environmental risk to preterm birth.

• DOI: 10.1371/journal.pone.0012391
• 发表时间: 2010-08-25
• 期刊: PloS one
• 影响因子: 3.7
• 作者: York TP;Strauss JF 3rd;Neale MC;Eaves LJ
• 通讯作者: Eaves LJ