ROLE OF HYALURONAN IN CONGENITAL BIRTH DEFECTS AND ATHEROSCLEROSIS

这个子项目是许多研究子项目中的一个 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， 因此可以在其他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。 具体目标： 目标1：在BN/Mcwi大鼠模型中，评价HA-CD 44相互作用导致细胞（正常主动脉SMC（ASMC））和遗传性动脉导管未闭（PDA）发育的SMC中平滑肌细胞（SMC）活化的作用。 目标1A。确定增加的HA合成是否足以在细胞和体内模型中赋予SMC活化。 目标1B。确定HA-CD 44相互作用是否是维持细胞和体内模型中SMC活化所必需的。 目标二：检查HA的考克斯-2介导的作用，并确定HA-CD 44相互作用通过涉及ErbB 2/PI 3-激酶（PI 3 K）/环氧合酶-2（考克斯-2）的途径调节ASMC和DA-SMC/Wistar中的SMC活化。 目标2A。确定HA是否调节ASMC-HAS 2、PDA-SMC-HAS 2/ BN转染子和DA-SMC/Wister中的考克斯-2酶活性。 目标2B确定考克斯-2单独是否介导HA诱导的对上述HAS 2转染和原代培养物中SMC活化的作用，如目标2A所述。 目的3：探讨HA-COX-2通路在LDR-/-小鼠与WT小鼠发育期DA与主动脉平滑肌细胞中的作用机制。 目标3A。确定HA是否调节LDR-/-与WT小鼠主动脉SMC中的考克斯-2酶活性。 目标3B确定考克斯-2是否单独介导HA诱导的对上述原代培养物中SMC活化的作用，如目标3A所述。 瞄准3C确定HA-COX-2通路是否通过SMC活化介导来自上述原代培养物的完整外植体中的内膜增厚，如目标3A所述。

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. Specific Aims: AIM 1: Evaluate the role of HA-CD44 interaction leading to smooth muscle cell (SMC) activation in cellular (normal aortic SMC (ASMC)) and SMC from inherited patent ductus arteriosus (PDA) development in BN/Mcwi rat models. Aim 1A. Determine if increased HA synthesis is sufficient to confer SMC activation in cellular and in vivo models. Aim 1B. Determine if HA-CD44 interaction is necessary for maintenance of SMC activation in cellular and in vivo models. Aim 2: Examine COX-2 mediated effects of HA, and establish that HA-CD44 interaction regulates SMC activation via a pathway involving ErbB2/PI3-kinase (PI3K)/cyclooxygenase-2 (COX-2)in ASMC and DA-SMC/Wistar. Aim 2A. Determine if HA regulates COX-2 enzyme activity in ASMC-HAS2, PDA-SMC-HAS2/ BN transfectants and DA-SMC/Wister. Aim 2B. Determine whether COX-2 alone mediates HA-induced effects on SMC activation in the above HAS2 transfected and primary cultures as in ¿ Aim 2A. Aim 3: Determine the mechanism of HA-COX-2 pathway for SMC activation in SMCs from developing DA versus aorta of LDR-/- versus WT mice. Aim 3A. Determine if HA regulates COX-2 enzyme activity in SMCs from aorta of LDR-/- versus WT mice. Aim 3B. Determine whether COX-2 alone mediates HA-induced effects on SMC activation in the above primary cultures as in ¿ Aim 3A. Aim 3C. Determine whether HA-COX-2 pathway mediates intimal thickening via SMC activation in intact explants from the above primary cultures as in ¿ Aim 3A.