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。 动脉导管(DA)连接着发育中的胎儿的肺动脉和主动脉，出生后不久，动脉导管通常关闭。导管关闭失败导致动脉导管未闭。循环中前列腺素E_2(PGE_2)的下降，以及之前新生内膜垫(NIC)组织的形成与导管闭合有关。因此，合乎逻辑的假设是EP4(PGE2受体)缺失的小鼠会过早地关闭DA。令人惊讶的是，EP4基因缺失的小鼠，或环氧合酶-2(COX-2)基因缺失的小鼠，反而会患上PDA。为了理解COX2诱导的PGE2信号的这种悖论，我们证明了PGE2/EP4诱导的透明质酸(HA)合成是胎儿DA为(最终出生后)导管NIC细胞的关闭和形成做准备所必需的(我们发表的数据；JCI，2006)。最近，我们还证明了PGE2在妊娠晚期激活DA中的EPAC(由cAMP激活的交换蛋白)(未发表的数据)，并且由于我们先前的研究表明PGE2也通过激活PKA来刺激HA(我们已发表的数据；JCI，2006)，我们有理由认为依赖于PKA的HA和依赖于EPAC的PI3K/AKT在DASMC的迁移过程中存在协同的串扰，从而诱导新的内膜垫形成。 DA闭合与平滑肌细胞(SMC)收缩成正比。一般来说，血管-SMC(VSMC)的收缩与肌球蛋白轻链激酶(MLCK)的磷酸化和蛋白激酶C(PKC)介导的ERK1/2的激活直接相关。对我们的研究来说，重要的是血管扩张细胞因子之一的合成是在DA的发育过程中诱导的。此外，肿瘤坏死因子的作用与VSMC的血管扩张有关。因此，肿瘤坏死因子在抑制VSMC收缩和抑制DA的张力方面起着重要作用。确保管腔在产前保持打开的机制与产后关闭管腔的机制(S)一样重要。未研究HA/CD44(主要HA受体)诱导的信号调节新生内膜细胞形成/功能的可能参与，以及HA在介导肿瘤坏死因子对导管-SMC收缩影响中的作用。因此，HA如何通过CD44/COX2/PGE2通路调节导管新生内膜形成和/或扩张的时间，以促进出生后导管的关闭并确保其在产前保持开放是我Cobre研究的重点(Suniti Misra博士；Pi和Shibnath Ghatak博士；Co-Pi)。

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 ductus arteriosus (DA) connects the pulmonary artery and aorta in the developing fetus Shortly after birth, the ductus normally closes. Failure to close ductus results in PDA. A decline in circulating prostaglandin E2 (PGE2), preceded by formation of neointimal cushion (NIC) tissue correlates with ductal closure. Thus, the logical assumption would be that EP4 (PGE2 receptor) null mice would have premature DA closure. Surprisingly, EP4 null mice, or cyclooxygenase-2 (COX-2) null mice, instead develop PDA. To understand this paradox of COX2 induced PGE2 signaling, we demonstrated that PGE2/EP4 induced hyaluronan (HA) synthesis is required to prepare the fetal DA for (eventual postnatal) closure and formation of the ductal NIC cells (our published data; JCI, 2006). Recently, we have also demonstrated that PGE2 activates EPAC (Exchange protein activated by cAMP) in the DA during late gestation (unpublished data), and since our previous studies showed that PGE2 also stimulates HA through activation of PKA (our published data; JCI, 2006), it is reasonable to assume the co-ordinated cross-talk among PKA-dependent HA and EPAC-dependent PI3K/AKT for DASMC migration for the induction of neointimal cushion formation. DA closure is directly proportional to smooth muscle cell (SMC) contraction. Generally, vascular-SMC (VSMC) contraction is known to be directly related to phosphorylation of the myosin light chain kinase (MLCK), and protein kinase C-¿ (PKC¿) mediated activation of Erk1/2. Important to our proposed study is that the synthesis of one of the vasodilatory cytokine TNF¿ is induced during the DA development. Additionaly, the effects of TNF¿ are implicated in vasodilation of VSMC. Thus TNF¿ must play an important role in inhibition of VSMC contraction and tone of the DA. The mechanism that assures that the ductal lumen stays open prenatally is as important as the mechanism(s) that close it postnatally. The potential involvement of the HA/CD44 (major HA receptor)-induced signaling that regulate the formation/function of neointimal cells and the role of HA in mediating the effects of TNF¿ on ductal-SMC contraction was not investigated. Thus, how HA signaling through CD44/COX2/PGE2 pathways regulates the timing of ductal neo-intimal formation and/or expansion to promote closure of the ductus after birth and to assure that it remains patent during prenatal life is the focus of my COBRE research ( Dr.Suniti Misra; PI and Dr. Shibnath Ghatak; Co-PI).