Project 1 - Lechner

项目 1 - 莱希纳

• 批准号: 9211206
• 负责人: Beatrice Elizabeth Lechner
• 金额: $ 32.49万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9211206
• 关键词: Attention; Biomechanics; Centers of Research Excellence; Complement Factor B; Connective Tissue Diseases; Data; Development; Ehlers-Danlos Syndrome; Embryo Transfer; Environmental Risk Factor; Escherichia coli; Exposure to; Extracellular Matrix; Fetal Membranes; Genetic; Genotype; Goals; Hand; Human; Incidence; Inflammation; Knock-out; Knockout Mice; Knowledge; Lead; Maintenance; Measures; Mechanics; Membrane; Morphology; Mus; Neonatal Mortality; Newborn Infant; Outcome; Patients; Phenotype; Pregnancy; Pregnancy Maintenance; Pregnancy Outcome; Premature Birth; Premature Rupture Fetal Membranes; Prevention strategy; Preventive; Preventive Intervention; Proteoglycan; Recombinants; Reproductive Health; Research; Role; Signal Pathway; Signal Transduction; Tensile Strength; Testing; Therapeutic; Therapeutic Intervention; Transforming Growth Factors; United States; Woman; Work; base; biglycan; biobank; decorin; disorder subtype; fetal; global health; innovation; neonatal morbidity; novel; premature; pup

PROJECT SUMMARY/ABSTRACT There is a key gap in knowledge with respect to mechanisms leading to preterm premature rupture of fetal membranes (PPROM). Continued existence of this gap represents an important problem because, until it is filled, the development of successful strategies for the prevention and treatment of PPROM will remain elusive. The long-term goal of this proposal is to reduce the incidence of PPROM-induced preterm birth. The objective here is to determine the extracellular matrix mechanisms that lead to PPROM. The central hypothesis for this proposal is that the extracellular matrix proteoglycans biglycan and decorin contribute to the maintenance of intact fetal membranes throughout gestation. This hypothesis is based on preliminary data that support a role for these mechanisms in maintenance of pregnancy. Preliminary studies show that the absence of biglycan and decorin in mice leads to preterm birth, abnormal fetal membrane morphology and altered signaling pathways, and that the phenotype is enhanced on exposure to inflammation. Furthermore, human fetal membranes with PPROM display decorin dysregulation. The rationale for the proposed research is that completion of these aims will define key biglycan- and decorin-dependent mechanisms that contribute to the integrity of fetal membranes, resulting in new and innovative strategies for the prevention and treatment of PPROM. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify the contributions of the proteoglycans biglycan and decorin to successful gestation using mice deficient in these proteoglycans; 2) Identify the mechanisms by which the extracellular matrix contributes to the structural integrity of the fetal membranes throughout gestation in the biglycan/decorin knockout mouse; and 3) Elucidate the status of the extracellular matrix in fetal membranes after PPROM in humans. Under the first aim, a maternal-fetal divergent genotype approach will be used to assess the extracellular matrix contribution to fetal membrane stability. For the second aim, fetal membrane biomechanical testing and recombinant biglycan rescue testing will be performed. For the third aim, human fetal membrane proteoglycan expression will be assessed. Each approach has been established as feasible in the applicants' hands. The contribution of the proposed research is expected to be the identification of novel biglycan- and decorin- dependent mechanisms that contribute to protection against PPROM. The proposed research is innovative because it represents a new and substantive departure from the status quo, namely the approach of extracellular matrix proteoglycan contribution to the stability of the fetal membranes using knockout fetal membrane mechanical testing, proteoglycan therapy and embryo transfer. The proposed research is significant because it is expected to vertically advance our understanding of extracellular matrix contribution to the stabilization of the fetal membranes throughout pregnancy. Ultimately, such knowledge has the potential to inform the development of new preventive and therapeutic strategies for PPROM.

项目摘要/摘要 关于导致早产过早破裂的机制的知识存在关键差距 膜（PPROM）。持续存在此差距是一个重要的问题，因为直到它是 填补，将继续制定预防和治疗PPROM的成功策略 难以捉摸。该提案的长期目标是减少PPROM诱导的早产的发生率。这 这里的目的是确定导致PPROM的细胞外基质机制。中央 该提议的假设是细胞外基质蛋白聚糖大型群体和Decorin有助于 整个妊娠过程中保持完整的胎儿膜。该假设基于初步数据 这支持这些机制在维持怀孕中的作用。初步研究表明 小鼠中缺乏大型群和装饰会导致早产，异常的胎儿膜形态和 信号通路的改变，并且在暴露于炎症时会增强表型。此外， 带有PPROM的人类胎儿膜表现出色的失调。拟议研究的理由 这些目标的完成将定义贡献的主要依赖和依赖于Decorin的机制 达到胎儿膜的完整性，为预防和治疗带来了新的和创新的策略 pprom。在强大的初步数据的指导下，该假设将通过追求三个具体目标来检验： 1）确定使用小鼠成功妊娠的蛋白聚糖和装饰的蛋白聚糖和装饰的贡献 这些蛋白聚糖缺乏； 2）确定细胞外基质有助于的机制 在大型群/装饰小鼠中，胎儿膜的结构完整性； 3）阐明了人类PPR的胎儿膜中细胞外基质的状态。在 第一个目的，将使用母体狂热分歧基因型方法来评估细胞外基质 对胎儿膜稳定性的贡献。对于第二个目标，胎儿膜生物力学测试和 将进行重组大型救援测试。对于第三个目标，人类胎儿膜蛋白聚糖 表达将被评估。在申请人的手中，每种方法都被确定为可行的。这 拟议的研究的贡献预计将是对新型大型群和装饰的识别。 有助于保护PPROM的依赖机制。拟议的研究是创新的 因为它代表了与现状的新事物，即 细胞外基质蛋白聚糖使用基因敲除胎儿对胎儿的稳定性贡献 膜机械测试，蛋白聚糖治疗和胚胎转移。拟议的研究是 意义重大，因为预计它将垂直提高我们对细胞外基质的理解 整个怀孕期间胎儿膜的稳定。最终，这种知识有潜力 为了开发PPROM的新预防和治疗策略。