Chemical and genetic studies of RORgamma and its critical roles in IBD

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The nuclear hormone receptor ROR gamma was recently shown to play crucial roles in the pathogenesis of multiple diseases including inflammatory bowel disease (IBD). However, its regulatory mechanisms remain largely unknown. My goal of this proposal is to identify genes regulating ROR¿ activity in mammalian cells and to develop small molecules that inhibit its function. These efforts may eventually lead to potential therapies for IBD and a variety of ROR gamma-dependent diseases. Since I started a post-doctoral career at the Littman laboratory at NYU medical center, I completed genome- wide RNAi and unbiased small molecule screens with heterologous ROR gamma reporter systems that are based on a insect cell line. From these screens, I identified ROR gamma regulators in three distinct Drosophila genetic pathways and several classes of antagonists with distinct chemical templates. I also confirmed that these small compound antagonists function not only in Drosophila cells, but also in mouse and human T cells. During the K99 period, I plan to study mammalian homologues of the identified genetic regulators in mouse T cells by taking RNA interference approaches (Aim 1). For one or two genes exhibiting the most specific activities for ROR gamma, during the R00 period, I will generate conditional knock-out mouse lines and test their effects on mouse models of IBD (Aim 3). In addition, I will try to identify potent ROR gamma chemical antagonists with high in vivo efficacy during the K99 and the early R00 stages (Aim 2). I already acquired several chemical derivatives as lead compounds. By synthesizing and testing various chemical derivatives, I anticipate that we will be able to identify compounds that can inhibit ROR¿ activity with high efficiency in vivo and to investigate their therapeutic potentials in the mouse models of IBD (Aim 3). My immediate research goal is to explore therapeutic options of IBD by genetically and chemically modulating the function of the nuclear hormone receptor ROR gamma, which has been shown to be crucial for certain types of IBD. My long-term research goal is to identify genetic targets and their modulators for additional types of IBD, utilizing insights from this study.