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)是孕产妇发病率和 早产。在当前支持期内进行的研究表明，基因的多态 编码基质金属蛋白酶(MMPs)会增加非程序性膜破裂的风险。我们现在 建议1)确定编码蛋白质的基因变异是否与胶原合成有关 以及翻译后修饰，包括SERPINH1基因，它编码一种伴侣， 调节胶原合成，以及催化胶原交联的赖氨酰氧化酶(LOX)基因家族， 探讨胎膜早破的风险。需要检验的假设是：1)SERPINH1的？656 T等位基因 基因是导致非裔美国人早产的种族选择因素；2)12个碱基缺失 毗邻656T的SNP对抗656T等位基因对胎膜早破的不利影响；3)12bP缺失 增加SERPINH1启动子的活性，减轻656 T等位基因的影响；4)胶原合成 羊膜成纤维细胞携带？656 T等位基因，但在存在12个碱基时不携带？656 T等位基因 缺失；5)656 T等位基因携带者羊膜纤维胶原含量减少，但当 6)T等位基因剂量与羊膜成纤维细胞胶原合成相关 和羊膜胶原含量，以及胎膜早破的风险；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； 8)这些变异体影响羊膜胶原的交联性。根据初步数据，人们将关注 重点研究了LOXL1基因。一项基于双胞胎的早产遗传学研究将被纳入一个新的 确定遗传力和基因发现的方法。2)确定表观遗传因素是否对 胎膜早破候选基因的表达。需要检验的假设是：1)甲基化的变异 CpG岛中的基质金属蛋白酶和胶原合成启动子基因调控基因表达；2)确定 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 候选基因因个体而异；4)这些基因的甲基化模式影响 转录与胎膜早破的风险相关；5)表观遗传标记改变了基因的影响 变种。这一假设将以MMP1启动子930T/C SNP为样本进行验证。这个 拟议的研究代表了临床和实验室研究的综合，将包括分子和 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，允许识别有胎膜早破风险的妇女，并识别遗传标记 预测胎膜早破。

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