Project 1 - Lechner

项目摘要/摘要 在导致胎儿早产早破的机制方面有一个关键的知识缺口。 膜(PPROM)。这种差距的持续存在是一个重要的问题，因为在它出现之前 作为补充，预防和治疗胎膜早破的成功战略的制定将继续 难以捉摸。这项提议的长期目标是减少胎膜早破引起的早产的发生率。这个 目的探讨胎膜早破的细胞外基质机制。中环 这一提议的假设是，细胞外基质蛋白多糖、二聚糖和粘附素有助于 在整个妊娠期间保持完整的胎膜。这一假设是基于初步数据。 这支持了这些机制在维持妊娠方面的作用。初步研究显示， 小鼠体内缺乏多糖和粘附素可导致早产、胎膜形态异常和 改变信号通路，并在暴露于炎症时表型增强。此外， 患有PPROM的人胎膜显示核心蛋白异常。建议进行这项研究的理由 这些目标的完成将定义关键的依赖于Biglycan和Decorin的机制 对胎膜的完整性，从而产生新的和创新的预防和治疗策略 可编程只读存储器。在强劲的初步数据的指导下，这一假设将通过追求三个具体目标来检验： 1)用小鼠鉴定蛋白多糖、大聚糖和核心蛋白在成功妊娠中的作用 缺乏这些蛋白多糖；2)确定细胞外基质参与 Biglycan/Decorin基因敲除小鼠整个妊娠过程中胎膜结构的完整性； 3)阐明胎膜早破后胎膜细胞外基质的状态。在.之下 第一个目标是，将使用母婴不同基因型方法来评估细胞外基质。 对胎膜稳定性的贡献。对于第二个目标，胎膜生物力学测试和 将进行重组Biglycan拯救试验。对于第三个目的，人胎膜蛋白多糖 将对表达进行评估。在申请者手中，每一种方法都被确定为可行的。这个 预计这项拟议研究的贡献将是鉴定新的大分子和装饰素- 有助于防止PPROM的依赖机制。建议的研究具有创新性。 因为它代表着与现状的新的实质性背离，即 细胞外基质蛋白多糖对基因敲除胎儿胎膜稳定性的影响 膜机械测试、蛋白多糖治疗和胚胎移植。拟议的研究是 意义重大，因为它有望垂直推进我们对细胞外基质对 妊娠期间胎膜的稳定。归根结底，这样的知识有可能 为胎膜早破新的预防和治疗策略的发展提供信息。

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.