Our research
Nuclear receptors are an evolutionarily conserved family of ligand-regulated transcription factors that have been demonstrated to regulate a host of physiological processes, including development, reproduction, metabolism, and immune responses. Our group’s focus is to use a combination of genetic, molecular biology, and chemical biology approaches to better understand nuclear receptors’ biological roles in the context of healthy vs. disease states. Ultimately, we aim to identify and develop small molecule modulators of nuclear receptors for the treatment of immune-mediated diseases.
General Nuclear Receptor Function
Nuclear receptors function as ligand-regulated transcription factors and share considerable amino-acid sequence homology. The general domain structure of nuclear receptors includes a variable amino-terminal domain, a central, highly conserved DNA binding domain (DBD), a hinge region, and a carboxy-terminal ligand binding domain (LBD). The LBD is responsible for the recognition and binding of the receptor’s ligand as well as ligand-dependent transcriptional activity.
Approximately half of the nuclear receptor superfamily have well characterized natural ligands whereas the remaining receptors are considered “orphan” receptors. Many nuclear receptors with identified natural ligands are also validated targets for clinical purposes. Therefore, nuclear receptors are an excellent source for therapeutics aimed at the treatment of a number of diseases, including inflammation, cancer, and metabolic disorders. While there are exceptions to the following description, typically, nuclear receptors are thought to be largely found in the nucleus, bound to DNA, in the absence of ligand. Without ligand, nuclear receptors recruit co-repressor proteins, like NCoR, to silence gene transcription. However, when their cognate ligand binds, a conformational change occurs in the nuclear receptor(s), dissociating the co-repressor protein, enabling the recruitment of co-activator proteins, like SRC1 or SRC2, driving gene transcription.
Nuclear Receptors in Autoimmunity and Chronic Inflammation
An organism’s immune system is a complex network of biological structures, processes, and cell types that has evolved to protect from foreign agents and the damage they may cause while sparing self-tissue. The failure of an organism to properly distinguish between “self” and “non-self” generates an autoimmune response. While the distinct mechanisms by which the body maintains tolerance to self-tissues has yet to be fully elucidated, recent findings have delineated novel cell types that provoke or protect from autoimmune pathology.
TH17 cells are a subset of CD4+ T helper cells that under homeostatic conditions have important roles at mucosal barriers for protection against extracellular bacteria and certain fungi. However, aberrant TH17 responses have been demonstrated to mediate autoimmune pathology. Several factors critical for the development of TH17 cells have been elucidated, including the orphan nuclear receptors (NRs), retinoic acid receptor-related orphan receptors a and g (RORa and RORgt). Our lab has identified other NRs that play key roles in regulating TH17 cell development and autoimmunity. These NRs, REV-ERBa and REV-ERBb, are often co-expressed in the same tissues as the RORs and bind the same DNA-response element, thus co-regulating their shared target genes. However, while the RORs are positive regulators of transcription, the REV-ERBs are transcriptional repressors as they can only recruit co-repressor proteins. We recently demonstrated that REV-ERBa is a critical negative regulator of TH17 cell development and that small molecule modulation of REV-ERBa/b activity was effective at suppressing TH17 cell development in vitro as well as TH17-mediated responses in vivo. More recently we also published a role for RORa in TH17 cells and the characterization of of RORa-selective small molecules to target TH17 cells and treat TH17-mediated autoimmunity. Insight into the transcriptional regulation of nuclear receptors and their ligand(s) function is essential to understand the signaling pathways that govern TH17 cell homeostasis vs. pathogenicity as well as the rational design of therapeutics for specific disease indications.
Since NRs are ligand dependent transcription factors, an attractive strategy for the development of novel therapeutics aimed at TH17-mediated autoimmunity is the selective targeting of NRs responsible for TH17 cellular development and function. We continue to focus our research on understanding how the REV-ERBs transcriptionally regulate TH17-mediated responses, ligand-mediated regulation of the REV-ERBs, and more recently, the non-redundant function of RORa in TH17 cells and how ligands influence its transcriptional activity in vitro and in vivo. Other interests in the lab include: understanding other NRs’ roles, (i.e. NR2F6) in TH17 cells and how they can be leveraged for anti-tumor immunity or novel therapeutics for autoimmunity; exploring the roles of the RORs and/or REV-ERBs in other immune cell populations (i.e. RORa in CD8 T cells). Implications for this project could have profound repercussions on vaccine design, delivery, and/or immune-oncology purposes.
