ROLE OF HYALURONAN IN CONGENITAL BIRTH DEFECTS AND ATHEROSCLEROSIS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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）通过其主要受体CD 44的相互作用调节动脉导管未闭（PDA）的发病机制，PDA是新生儿常见的心血管缺陷。考克斯-2抑制剂有效地关闭了近足月婴儿的DA。在大鼠模型中，我们已经表明PGE 2通过促进NIC形成伴随着升高的HA来准备胎儿DA关闭，HA用于闭塞DA。PGE 2受体（EP 4）的缺失导致小鼠中的致命PDA，表明这是NIC形成所必需的。总体假设是，HA-CD 44/COX 2途径调节NIC形成的时间，以促进出生后导管闭合并确保产前生命期间的通畅。为了解释这种平衡行为，我们提出了两个目标。在目的1中，我们将确定HA-CD 44相互作用如何促进NIC形成，并评估HA是否通过DA内皮细胞转分化为血管SMC诱导NIC形成。 此外，我们将研究HA/CD 44相互作用是否诱导E18小鼠DA（NIC形成的活跃期）所需的考克斯-2/PGE 2信号传导。 在目标2中，我们将确定HA信号传导是否通过触发上调血管舒张细胞因子TNF-α分泌的反馈环机制来抑制NIC形成。 此外，我们将研究是否需要HA-COX-2-HA反馈回路来诱导TNF-α，这可能通过在体内和体外阻断EnMT来防止NIC的形成。 这些研究将描述HA在早产开放和足月后DA闭合中的双重作用。

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.