The nuclear receptor family is made up of ligand-activated transcriptional regulators that have been implicated as key regulators of development and metabolic homostatsis of the human body. Many common diseases such as atherosclerosis, hepatic and pulmonary fibrosis, cancer and chronic inflammation have their origins in loss metabolic or developmental control. We will focus on exploring the mRNA expression profile of nuclear hormone receptors in human diseases including but not limited to nonalcoholic steatohepatitis (NASH), atherosclerosis and diabetes, skin diseases (eg psoriasis), brain tumors and myeloid leukemia. In addition, selective mouse models will be used to examine the expression pattern of mRNA NR family during early and late phases of progression of metabolic and inflammation diseases such as atherosclerosis. Profiling will be achieved through the quantitative PCR NR NURSA platform which provides a sensitive and highly quantitative method for analyzing NR mRNA levels. The data collected from these studies will be contained within a shared Bioinformatics Resource for data mining by the wider scientific community. In addition one of the major goals of this project is to develop of new analytical tools for determining and altering the expression of all members of the nuclear receptor family in specific cells and tissues. In addition, we will design, develop and validate a comprehensive lentiviral shRNA knockdown library that targets the entire NR family. Finally, we will use the library to interrogate cell lines and animal models of metabolic, inflammatory and cancer states in which a receptor has been shown to have a dynamic and/or dominant expression profile. The NR lentiviral shRNA knockdown library will be made available other NURSA members with the eventual goal of supplying the research community with a powerful new tools for analyzing NR function.
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