| The Aryl Hydrocarbon Receptor, AHR, is well known for its ability to mediate the effects of diverse environmental toxicants. This thesis will outline the work we have done to understand the role of the AHR co-chaperone, the Aryl Hydrocarbon Receptor Associated Protein 9 (ARA9) within and outside of the AHR signaling pathway. In chapter one I will review the literature regarding ARA9. In chapter two I will present evidence that Ara9 -/- mice undergo embryonic lethality that appears to be due cardiac malformations. Our observations from this data support our previous hypothesis that ARA9 plays a role in a pathway outside of AHR signaling. In chapter three, I will discuss the hypomorphic Ara9 mouse line ( Ara9fxneo). This model bypasses the embryonic lethality seen in the Ara9-/- but presents with a patent Ductus Venosus (DV). Our observations from this data support the hypothesis that ARA9 is a critical component of AHR developmental signaling. In the fourth chapter, we provide evidence to support our model that the nuclear localization signal (NLS) of the AHR sits within a binding pocket. Furthermore, this "masking" phenomenon is relieved by insertion of even a single amino acid. In the final chapter I will discuss several possible studies for future undertaking. |
