The retinoic acid-related orphan receptors (ROR α-γ or NR1F1-3) and the orphan receptor TAK1 (TR4 or NR2C2) are members of the nuclear receptor superfamily of ligand-dependent transcription factors. These receptors exhibit critical functions in regulating embryonic development and many other physiological processes and have been implicated in a variety of pathologies. The ROR and TAK1/TR4 nuclear receptors are targets for endocrine disruptors and drug therapy.

Mechanisms of action. The RORs regulate gene transcription by binding as a monomer to ROR response elements (ROREs) consisting of the consensus sequence AGGTCA preceded by a 6-bp A/T rich region in the regulatory region of target genes, whereas TAK1/TR4 homodimers bind direct repeats of AGGTCA spanned by 1-5 nucleotides. The transcriptional regulation by nuclear receptors is mediated through their interaction with co-repressors or co-activator complexes.

Physiological functions. RORs play a critical role in several immune functions. RORα and γ regulate thymopoiesis and innate and adaptive immune responses. RORγ is essential for lymph node development and Th17 differentiation, while RORγ regulates cerebellar development and bone formation. Moreover, RORα,γ and TAK1/TR4 play an important role in the regulation of various metabolic pathways and energy homeostasis. These receptors may play a key role in the interplay between inflammatory and metabolic processes.

Roles in disease. The RORs and TAK1/TR4 have been implicated in a number pathologies, including various autoimmune diseases, asthma, osteopenia, metabolic syndrome, cancer, and autism.

Inflammation and autoimmunity: The RORs and TAK1/TR4 receptors play a key role in regulating various immune responses and inflammation. RORs are essential for Th17 differentiation and interleukin 17 (IL-17) production, which are critical in the development of various autoimmune diseases, but have also been implicated in other inflammatory processes, including asthma. ROR-deficiency greatly reduced Th17 differentiation, the development and severity of experimental autoimmune encephalomyelitis (EAE), and allergy-induced lung inflammation.

Metabolic syndrome: Deficiency in RORα and TAK1/TR4 greatly decreases the susceptibility to age- and diet-induced metabolic syndrome and inhibits adipose tissue-associated inflammation. These mice are protected from the development of hepatic steatosis and type 2 diabetes. The RORs and TAK1/TR4 nuclear receptors regulate both immunological and metabolic processes and as such might provide a regulatory link between these two processes.

Potential therapy: Recent studies have indicated that RORs and TAK1/TR4 act as ligand-dependent transcription factors and several synthetic (ant)agonists have been identified. RORs and TAK1/TR4 (ant)agonists might potentially offer new therapeutic strategies of various diseases, particularly asthma, autoimmune diseases, autism, diabetes, cancer, and metabolic syndrome.

Gene-environment interaction: In addition to natural ligands, endocrine disrupting chemicals can function as ligands for nuclear receptors thereby providing a mechanism by which environmental agents can influence physiological processes and promote disease. Moreover, through their regulation of a variety of metabolic enzymes, RORs and TAK1 can influence the metabolism of xenobiotics and drugs (Phase I and II enzymes), thereby enhancing or abolishing their activities and subsequently affect disease and therapy.

Our research objectives are:

1. To obtain further insights into the mechanisms by which these nuclear receptors regulate gene expression in relationship to the various physiological processes they control.
2. To determine the mechanisms that underlie the development of various pathologies in mice and humans deficient in ROR or TAK1 functions.
3. To identify ROR/TAK1 ligands and determine their therapeutic potential in inflammatory diseases and metabolic syndrome.
4. To identify links between these signaling pathways and gene-environment interactions.