ROLE OF HYALURONAN IN CONGENITAL BIRTH DEFECTS AND ATHEROSCLEROSIS

透明质酸在先天性缺陷和动脉粥样硬化中的作用

• 批准号: 7959862
• 负责人: SUNITI MISRA
• 金额: $ 21.23万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959862
• 关键词: Atherosclerosis; Birth; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; Defect; Dinoprostone; Endothelium; Equilibrium; Extracellular Matrix; Feedback; Funding; Goals; Grant; Hyaluronan; In Vitro; Infant; Institution; Life; Modeling; Mus; Newborn Infant; PTGS2 gene; Patent Ductus Arteriosus; Pathogenesis; Pathway interactions; Prostaglandin E Receptor; Rattus; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Time; United States National Institutes of Health; base; cytokine; fetal; human WFDC2 protein; in vivo; inhibitor/antagonist; prenatal; prevent; receptor; transdifferentiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to understand how interactions of the major extracellular matrix component, hyaluronan (HA) via it's principle receptor, CD44regulates the pathogenesis of patent ductus arteriosus (PDA), a frequent cardiovascular defect in newborns. COX-2 inhibitors effectively close the DA in near-term infants, With a rat model, we have shown that PGE2 prepares fetal DA closure by promoting NIC formation accompanied by elevated HA that serves to occlude the DA. Deletion of the PGE2 receptor (EP4) results in fatal PDA in mice, indicating that is required for NIC formation. The overarching hypothesis is that HA- CD44/COX2 pathways regulates the timing of NIC formation to promote ductus closure after birth and assurance of patency during prenatal life. To explain this balancing act, we propose two Aims. In Aim 1, we will determine how HA-CD44 interactions promote NIC formation, and assess whether HA induces NIC formation by transdifferentiation of DA endothelium into vascular SMCs. Also, we will investigate whether HA/CD44 interaction induces COX-2/PGE2 signaling required for E18 mouse DA (the active period for NIC formation). In Aim 2, we will determine whether HA signaling inhibits NIC formation by triggering a feedback loop mechanism that upregulates secretion of a vasodilatory cytokine, TNF-a. Also, we will investigate whether a HA-COX-2-HA feedback loop is required for induction of TNF-a that may prevents the formation of NIC by blocking EnMT in vivo and in vitro. These studies will characterize the dual role of HA in preterm opening and post term DA closure.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的长期目标是了解主要细胞外基质成分透明质酸（HA）如何通过其原理受体的相互作用，CD44调节新生儿中频繁的心血管缺陷的专利导管（PDA）的发病机理。 COX-2抑制剂有效地在近期婴儿中有效地关闭了DA，我们已经通过大鼠模型表明，PGE2通过促进NIC的形成并伴随着升高的HA来制备胎儿DA闭合，从而遮挡DA。 PGE2受体的缺失（EP4）导致小鼠致命的PDA，表明这是NIC形成所必需的。总体假设是，HA-CD44/COX2途径调节了NIC形成的时机，以促进出生后的导管闭合和产前寿命期间的通畅性。为了解释这种平衡行为，我们提出了两个目标。在AIM 1中，我们将确定HA-CD44相互作用如何促进NIC的形成，并评估HA是否通过将DA内皮转分化为血管SMC来诱导NIC形成。 另外，我们将研究HA/CD44相互作用是否诱导E18小鼠DA所需的COX-2/PGE2信号传导（NIC形成的活动周期）。 在AIM 2中，我们将确定HA信号传导是否通过触发反馈回路机制来抑制NIC的形成，该机制上调了tnf-a的血管舒张细胞因子的分泌。 另外，我们将研究HA-COX-2-HA反馈回路是否需要通过在体内和体外阻断ENMT来阻止NIC形成NIC的TNF-A是否需要。 这些研究将表征HA在早产开放和术后DA闭合中的双重作用。