ROLE OF HYALURONAN IN CONGENITAL BIRTH DEFECTS AND ATHEROSCLEROSIS

这个子项目是众多研究子项目之一

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.