Nuclear receptor (NR) signaling is essential for normal development as well as normal metabolic and physiologic function in humans. In addition, NRs are potential targets in a variety of hormone-dependent cancers. Central to the action of NRs is their ability to recruit the transcriptional corepressors, NCoR and SMRT, in the absence of ligand or in the presence of antagonists to target key pathways. In the following proposal we will use the thyroid hormone receptor (TR) and the androgen receptor (AR) to understand the role of the corepressor, NCoR, in vivo as there are currently no mouse model systems in which to analyze NCoR function and its role in NR signaling. In the first Aim, we will develop mouse models which lack NCoR in the liver and heart where TR-signaling is paramount. These mice should give key insight into the specific role of NCoR in TR action and determine whether NCoR plays a role in the determental effects of hypothyroidism on both lipid metabolism in the liver and cardiac function. In contrast to the TR, the AR recruits NCoR in the presence of partial agonists or antagonists. We hypothesize that the enhanced recruitment of NCoR to the AR will be therapeutic in prostate cancer where AR action is critical for tumor development and progression. Thus, in the second Aim, we will determine the molecular mechanisms by which NCoR is recruited to the AR in order to be able to better design antagonists which will enhance therapeutic opportunities in prostate cancer. Recruitment of NCoR to the AR and TR is mediated in cells by different molecular mechanisms. However, this has not been demonstrated in vivo which is essential in order to design therapies that may influence one pathway but not the other. In the third Aim, we will use a mouse model to introduce a mutation into NCoR that will disrupt its recruitment by the TR only and thus only disrupt TR-signaling and preserve the recruitment of NCoR by other NR signaling pathways. This study should confirm our hypothesis that separate regions of NCoR allow recruitment to different nuclear receptors. The completion of these three Aims will allow for great insight into how modulation of NCoR signaling, through either enhanced or diminished recruitment to a target NR, can lead to novel therapeutic strategies for a number of disease states including hyperlipidemia, cardiomyopathy and prostate cancer.
