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起着关键作用。 包括炎症性肠病(IBD)在内的疾病。然而，其监管机制在很大程度上仍然 未知。我这项提议的目标是识别哺乳动物细胞中调节ROR活性的基因，并 开发抑制其功能的小分子。这些努力可能最终会导致潜在的治疗方法 IBD和各种ROR伽马依赖型疾病。 自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以来，我完成了基因组- 广泛的RNAi和无偏见的小分子筛选与基于昆虫细胞系的异源ROR伽马报告系统。从这些屏幕上，我在三种不同的果蝇基因中识别出了RoR伽马调节器 途径和几类具有不同化学模板的拮抗剂。我还确认了这些小的 复合拮抗剂不仅在果蝇细胞中发挥作用，而且在小鼠和人类T细胞中也发挥作用。在.期间 K99期间，我计划通过以下方式研究小鼠T细胞中已识别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)。对于一个或两个基因表现出最特定的活性 ROR伽马，在R00期间，我将生成条件基因敲除小鼠品系，并测试它们对IBD小鼠模型的影响(目标3)。此外，我将尝试在K99和R00早期阶段(目标2)寻找在体内具有高效率的有效ROR伽马化学拮抗剂。我已经买了几个化学衍生品作为 先导化合物。通过合成和测试各种化学衍生品，我预计我们将能够 寻找体内高效抑制ROR活性的化合物并研究其治疗作用 IBD小鼠模型的潜能(目标3)。 我目前的研究目标是通过基因和化学调节来探索IBD的治疗方案 核激素受体ROR伽马的功能，已被证明对某些类型的 IBD。我的长期研究目标是确定其他类型IBD的遗传靶点和它们的调节器， 利用这项研究的洞察力。

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.