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.

在所有哺乳动物物种中，成功的分娩都需要及时发作子宫收缩并重塑子宫颈，以允许胎儿通过出生管。控制这些相互交织过程的分子机制仍然很少理解。每年，由于正常的分娩失败，全世界大约有450万个过早的婴儿出生，并且与后期怀孕有关的并发症会导致母亲和儿童无数问题。拟议的研究旨在进一步理解促进宫颈软化和成熟的分子过程。在正常小鼠和宫颈成熟缺陷的小鼠中的研究表明，酶透明质酸合酶2在糖胺聚糖透明质酸（HA）的产生中起着重要作用。我们假设HA在成熟过程中具有多个角色。第一个角色是一个结构性的角色，其中HA提供了一个松散相关的MATDX，以允许对基质进行适当的重组。我们提出的HA的第二个作用是在成熟过程中正常炎症反应所需的细胞信号传导事件中。将进行体内和体外研究，以了解宫颈成熟中透明质酸合酶2的调节。旨在评估HA生理功能的研究将启动。这包括鉴定子宫颈中HA结合蛋白对于HA功能至关重要，评估HA分子量的变化以及HA细胞表面受体的表征CD44。最后，我们将确定HA含量异常升高或降低的HA含量在与宫颈无能相关，威胁性早产劳动或后期怀孕后未能进展后未能进展的女性中起作用。这些研究中采用的综合方法与本提案中的其他项目结合使用，将为控制小鼠和妇女的分娩机制提供新的分子洞察力，并将建立一个框架，以设计疗法以防止与分娩相关的并发症。