REGULATION OF ENVIRONMENTAL DISEASES BY SOLUBLE RECEPTORS

There is a distinct need for new approaches to prevent and treat hepatocellular carcinoma as the current strategies of chemotherapy and surgical treatments are not very effective. Similarly, there is a need for new chemopreventive approaches for non-melanoma skin cancer, one of the leading types of cancer that affects all Americans. Thus, it is essential to delineate new molecular pathways involved in the etiology of liver and skin cancer to provide new strategies with significantly better efficacy to prevent human mortality due to liver and skin cancer. These studies will utilize genetic and chemical models of cancer coupled with administration of synthetic and natural chemicals that can activate PPARbeta/delta to determine if they can prevent disease progression. Results from these innovative studies will determine if peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) can be an anti-inflammatory molecular target and provide an alternative strategy for preventing and treating liver and skin cancer. Additionally, results from these studies could lead to a significant paradigm shift in treatment strategies for liver and skin cancer if epigenetic modulation of inflammatory signaling mediated by PPARbeta/delta is shown to effectively prevent hepatocarcinogenesis and/or UVB-induced skin cancer. Results from these studies could provide new information to support the development of new dietary sources, including genetically engineered food, for the treatment and prevention of cancers. Previous studies have revealed that activation of the Ah receptor (AhR) can lead to enhanced inflammatory signaling. However, whether the AhR plays an underlying endogenous role in inflammation was unknown. Considering that there are a large number of diseases that have an inflammatory component to their progression the discovery of the AhR as a new anti-inflammatory target is a major discovery that could lead to the development of new therapeutic agents. The Perdew laboratory has also discovered a new class of AhR ligands that selectively activate the AhR to induce anti-inflammatory activity. Two selective ligands have been identified and are being used to assess their activity. These studies will allow the identification of higher affinity chemicals that can activate the AHR that will allow studies to be designed to further explore their therapeutic potential. In addition, additional complete AHR antagonist will be developed and their ability to be utilized in animal studies examined. These studies will provide the groundwork for testing the use of an AHR antagonist to inhibit tumor metastasis and tumor growth using in vivo models in isolation and in combination with established therapies.