The nuclear hormone receptor ROR3 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 ROR3 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 ROR3-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 ROR3 reporter systems that are based on a insect cell line. From these screens, I identified ROR3 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 ROR3, 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 ROR3 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 ROR3 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 ROR3, 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.

Public Health Relevance

The nuclear hormone receptor ROR3 was recently shown to play crucial roles in the pathogenesis of several mice models of the inflammatory bowel disease (IBD). I propose to identify genes regulating its activity and to develop small chemical molecules that inhibit its function. Such genetic and small chemical modulators may provide novel therapeutic means to treat human IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK091508-02
Application #
8331549
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Karp, Robert W
Project Start
2011-09-15
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$90,000
Indirect Cost
$6,667
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Longman, Randy S; Diehl, Gretchen E; Victorio, Daniel A et al. (2014) CX?CR1? mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med 211:1571-83
Huh, Jun R; Englund, Erika E; Wang, Hang et al. (2013) Identification of Potent and Selective Diphenylpropanamide RORýý Inhibitors. ACS Med Chem Lett 4:79-84