ROLE OF HYALURONAN IN CONGENITAL BIRTH DEFECTS AND ATHEROSCLEROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的长期目标是了解主要的细胞外基质成分透明质酸(HA)通过其主要受体CD44如何调控动脉导管未闭(PDA)的发病机制，PDA是新生儿常见的心血管缺陷。COX-2抑制剂有效地关闭了近月儿的DA，在一个大鼠模型中，我们已经证明PGE2通过促进NIC的形成并伴随用于阻断DA的高HA来准备关闭胎儿DA。PGE2受体(EP4)的缺失会导致小鼠死亡的PDA，这表明这是NIC形成所必需的。最重要的假设是，HA-CD44/COX2通路调节NIC的形成时间，以促进出生后导管关闭和确保产前通畅。为了解释这种平衡行为，我们提出了两个目标。在目标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的形成。此外，我们还将研究HA/CD44相互作用是否诱导E18小鼠DA(NIC形成的活跃期)所需的COX-2/PGE2信号转导。在目标2中，我们将确定HA信号是否通过触发反馈循环机制来抑制NIC的形成，该反馈循环机制上调血管扩张细胞因子TNF-a的分泌。此外，我们还将研究是否需要HA-COX-2-HA反馈环来诱导肿瘤坏死因子-α，从而在体内和体外通过阻断EnMT来防止NIC的形成。这些研究将表征HA在早产开放和足月DA关闭中的双重作用。

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.