Regulation and Function of Hyaluronan in Cervical Remodeling

透明质酸在宫颈重塑中的调节和功能

• 批准号: 8442192
• 负责人: MALA S. MAHENDROO
• 金额: $ 26.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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/8442192
• 关键词: Affect; Apoptosis; Binding; Biological Assay; Biomechanics; Birth; CD44 gene; Cavia; Cell Line; Cell physiology; Cells; Cervical; Cervical Ripening; Cervix Mucus; Cervix Uteri; Child; Clinical; Complex; Development; Epithelial; Epithelial Cells; Epithelium; Evaluation; Event; Extracellular Matrix; Fluorescence Resonance Energy Transfer; Funding; Future; Gene Expression; Genetic Transcription; Glycosaminoglycans; Human; Hyaluronan; Hyaluronidase; Immune; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Instruction; Investigation; Knock-out; Label; MAPK14 gene; Measurement; Measures; Mediating; Modeling; Molecular; Molecular Weight; Monitor; Mus; NF-kappa B; Outcome; Pathway interactions; Performance; Phase; Phenotype; Physiological Processes; Play; Postpartum Period; Pregnancy; Pregnant Women; Premature Birth; Preparation; Prevention; Prevention therapy; Principal Investigator; Process; Production; Progesterone Receptors; Property; Proteoglycan; Receptor Activation; Regulation; Research; Risk; Role; Signal Pathway; Sterility; Stromal Cells; Structure; Tensile Strength; Testing; Time; Tissues; Toll-like receptors; United States; Uterine Contraction; Woman; base; cell type; efficacy testing; hyaluronan synthase 1; improved; in vivo; inhibitor/antagonist; insight; macrophage; migration; monocyte; mouse toll-like receptor 4; premature; prevent; promoter; receptor; recombinase; repaired; therapeutic target; therapy development; tissue repair; toll-like receptor 4; tool; versican; viscoelasticity

Preterm birth occurs in 12.5% of pregnancies, affects 500,000 children per year in the United States and has a financial toll that exceeds $26 billion per year. A greater understanding of the molecular processes that regulate parturition are essential for prevention of prematurity. Towards this end our research is aimed at understanding how the cervix remodels in preparation for birth. One unique aspect of cervical ripening and dilation at the end of pregnancy is the marked increase in expression of hyaluronan synthase 2 resulting in increased hyaluronan (HA) production. We propose that hyaluronan has multiple roles in the cervix that are dependent on the HA size, structure, binding partners and cell type. In the current study we will test the hypothesis that high molecular weight HA has important functions during ripening to increase tissue viscoelasticity and that the breakdown to low molecular weight HA serves two functions: 1) to allow loss of tissue integrity and maximal tissue compliance with onset of uterine contraction and 2) to modulate inflammatory events needed for postpartum tissue repair. These functions of HA in cervical remodeling will be tested in mice with a cervix specific depletion of Has2. Temporal changes in hyaluronidase activity will be measured in the mouse and guinea pig cervix during cervical ripening, in labor and postpartum and correlated with changes in biomechanical properties of the cervix as well as migration, activation and phenotype of inflammatory cells before, during and after birth. The interaction of HA with CD44 and toll like receptors and activation of downstream signaling pathways will be evaluated in both macrophage and cervical epithelial cell lines and compared to pathways induced by lipopolysacharide (LPS). The ability of HA to compete with LPS and reduce rates of infection-mediated PTB will be tested in wild type, CD44''' and TLR4'' mice. Finally investigations will be carried out using cervical mucus from pregnant women to determine if increased hyaluronidase activity and low molecular weight HA correlates with progression of pregnancy and degree of cervical ripening as determined by a Bishops score. Taken together, these studies will enhance our understanding of the physiological process of cervical remodeling, provide insight into how a matrix molecule can modulate processes important in distinct phases of cervical remodeling before and after birth and will provide the basis for future studies aimed at development of therapies for prevention of complications associated with both preterm and postterm birth. RELEVANCE (See instructions): Understanding the molecular processes that modulate term cervical remodeling is critical to identify causes of premature remodeling that result in pretemn birth. Hyaluronan (HA) has important proposed roles during multiple phases of remodeling before and after birth and in the current study these functions will be better defined. Therapeutic targets may be an outcome as our study will test the efficacy of HA treatment to reduce rates of infection mediated preterm birth and will provide insights as to whether hyaluronidase injection into the cervix mav have utilitv in oromotina cervical ripening post term oreanancv or at the time of labor. Project/Performance

早产发生在12.5％的怀孕中，每年影响50万儿童 每年的财务损失超过260亿美元。对分子过程的更多了解 调节分娩对于预防早产至关重要。为此，我们的研究针对 了解子宫颈如何为出生做准备。宫颈成熟的一个独特方面 怀孕结束时的扩张是透明质酸合酶2的表达显着增加，导致 在增加的透明质酸（HA）生产中。我们建议透明质酸在子宫颈中有多个角色 取决于HA大小，结构，结合伙伴和细胞类型。在当前的研究中，我们将测试 假设高分子量HA在成熟过程中具有重要功能以增加组织 粘弹性和对低分子量的分解HA具有两个功能：1）允许丢失 组织完整性和最大组织符合子宫收缩的发作，2）调节 产后修复所需的炎症事件。宫颈重塑中HA的这些功能将 在宫颈特异性耗竭的小鼠中进行测试。透明质酸酶活性的时间变化将是 在宫颈成熟期间，分娩和产后，在小鼠和豚鼠子宫颈中测量 与子宫颈生物力学特性的变化以及迁移，激活和 出生前，期间和之后的炎症细胞表型。 HA与CD44的相互作用和收费 受体和下游信号通路的激活将在巨噬细胞和 宫颈上皮细胞系，并与脂肪术（LPS）诱导的途径进行比较。 HA的能力 要与LP竞争并降低感染介导的PTB的发生率将以野生型测试，CD44''''和 TLR4''鼠标。最后，将使用孕妇的宫颈粘液进行调查 确定透明质酸酶活性增加和低分子量HA是否与进展相关 由主教评分确定的怀孕和宫颈成熟程度。总之，这些研究 将增强我们对宫颈重塑生理过程的理解，提供有关如何 基质分子可以调节在前后宫颈重塑不同阶段重要的过程 出生后，将为未来的研究提供旨在开发预防疗法的基础 与早产和后分娩相关的并发症。 相关性（请参阅说明）： 了解调节术语宫颈重塑的分子过程对于确定原因至关重要 过早的重塑导致出生。透明质酸（HA）在 出生前后的多个重塑阶段，在当前的研究中，这些功能将更好 定义。治疗靶标可能是一个结果，因为我们的研究将测试HA治疗的功效以减少 感染率介导的早产率，并将提供有关透明质酸酶是否注射到中的见解 子宫颈MAV在Oromotina宫颈成熟后的术语后期或劳动时具有液化性。 项目/性能