Project 3 REGULATION AND FUNCTION OF HYALURONAN

项目3 透明质酸的调控与功能

• 批准号: 6896286
• 负责人: MALA S. MAHENDROO
• 金额: $ 23.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896286
• 关键词: antibody; carbohydrate biosynthesis; cervix; disease /disorder prevention /control; extracellular matrix; gene expression; genetic regulation; genetic transcription; genetically modified animals; glucuronosyltransferase; human tissue; hyaluronate; in situ hybridization; laboratory mouse; molecular biology; polymerase chain reaction; premature labor; progesterone; prostaglandin E; relaxin; reporter genes; stromal cells

Successful parturition in all mammalian species requires a timely onset of uterine contractions and remodeling of the cervix to allow passage of the fetus through the birth canal. The molecular mechanisms controlling these intertwined processes remain poorly understood. Each year, some 4.5 million severely premature infants are born worldwide due to failure of normal parturition, and complications associated with delivery in post term pregnancies cause innumerable problems in both mother and child. The proposed studies are designed to further our understanding of the molecular processes that facilitate cervical softening and ripening. Studies in normal mice and mice with defects in cervical ripening have revealed an important role of the enzyme hyaluronan synthase 2 in production of the glycosaminoglycan hyaluronan (HA). We hypothesize HA has multiple roles in the ripening process. The first role is a structural one in which HA provides a hydrated loosely associated matdx to allow appropriate restructuring of the matrix. A second role of HA we propose, is in initiation of cell signaling events required for a normal inflammatory response during the ripening process. In vivo and in vitro studies will be carried out to understand regulation of hyaluronan synthase 2 in cervical ripening. Studies designed to evaluate the physiological functions of HA will be initiated. This includes identification of HA-binding proteins in the cervix that are critical to HA function, evaluation of changes in HA molecular weight and characterization of the HA cell surface receptor, CD44. Finally, we will determine if abnormally elevated or reduced HA content plays a role in complications associated with cervical incompetence, threatened preterm labor, or in women with postterm pregnancies who fail to progress after induction of labor. The integrated approaches applied in these studies in combination with the other projects in this proposal will provide novel molecular insight into the mechanisms controlling parturition in mice and women and will establish a framework from which to devise therapies to prevent complications associated with parturition.

所有哺乳动物物种的成功分娩都需要及时开始子宫收缩和子宫颈重塑，以允许胎儿通过产道。控制这些相互交织的过程的分子机制仍然知之甚少。全世界每年约有 450 万严重早产儿因正常分娩失败而出生，足月妊娠期间分娩的相关并发症给母亲和孩子带来无数问题。拟议的研究旨在进一步了解促进宫颈软化和成熟的分子过程。对正常小鼠和宫颈成熟缺陷小鼠的研究表明，透明质酸合酶 2 在糖胺聚糖透明质酸 (HA) 的产生中发挥着重要作用。我们假设 HA 在成熟过程中具有多种作用。第一个作用是结构作用，其中 HA 提供水合松散关联的 matdx，以允许适当的基质重组。我们提出的 HA 的第二个作用是启动成熟过程中正常炎症反应所需的细胞信号传导事件。将进行体内和体外研究，以了解透明质酸合酶 2 在宫颈成熟中的调节作用。将启动旨在评估HA生理功能的研究。这包括鉴定宫颈中对 HA 功能至关重要的 HA 结合蛋白、评估 HA 分子量的变化以及 HA 细胞表面受体 CD44 的表征。最后，我们将确定HA含量异常升高或降低是否在与宫颈机能不全、先兆早产或引产后进展失败的过期妊娠妇女相关的并发症中发挥作用。这些研究中应用的综合方法与本提案中的其他项目相结合，将为控制小鼠和女性分娩的机制提供新的分子见解，并将建立一个框架，从中设计出预防与分娩相关的并发症的疗法。