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

核激素受体ROR γ最近被证明在多发性硬化症的发病机制中发挥关键作用 疾病，包括炎症性肠病（IBD）。然而，其监管机制在很大程度上仍然是 未知我的这个建议的目标是确定在哺乳动物细胞中调节ROR活性的基因， 产生抑制其功能的小分子。这些努力可能最终导致潜在的治疗方法， IBD和多种ROR γ依赖性疾病。 从我在纽约大学医学中心的利特曼实验室开始博士后生涯，我完成了基因组- 利用基于昆虫细胞系的异源ROR γ报道系统进行宽RNAi和无偏小分子筛选。通过这些筛选，我在三种不同的果蝇基因组中鉴定出了ROR γ调节子。 途径和几类具有不同化学模板的拮抗剂。我还证实，这些小 复合拮抗剂不仅在果蝇细胞中起作用，而且在小鼠和人T细胞中也起作用。期间 K99期间，我计划研究小鼠T细胞中已鉴定的遗传调节因子的哺乳动物同源物， 采用RNA干扰方法（目标1）。对于一个或两个表现出最特异性活性的基因， ROR γ，在R 00期间，我将产生条件性敲除小鼠品系，并测试其对IBD小鼠模型的影响（目标3）。此外，我将尝试确定在K99和早期R 00阶段具有高体内功效的有效ROR γ化学拮抗剂（目的2）。我已经获得了一些化学衍生物， 铅化合物。通过合成和测试各种化学衍生物，我预计我们将能够 鉴定能够在体内高效抑制ROR活性的化合物，并研究它们的治疗作用。 在IBD小鼠模型中的潜力（目的3）。 我的近期研究目标是通过基因和化学调节来探索IBD的治疗选择， 核激素受体ROR γ的功能，这已被证明是至关重要的某些类型的 IBD。我的长期研究目标是确定其他类型IBD的遗传靶点及其调节剂， 利用这项研究的见解。

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.