The nuclear receptor superfamily (NR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor- related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, neural development, metabolism and the immune response. Our data suggests that activation of ROR? by synthetic ligands reduces autistic-behavior in mouse models while increasing the expression of key genes that are known to be downregulated in individuals with this disorder. ROR? inverse agonists that we discovered have been characterized for their ability to reduce proinflammatory TH17 cell differentiation, which has been shown to be associated with depression. In fact, treatment of mice with SR1001 (a ROR? inverse agonist) reduces depression-like behavior. We hypothesize that optimized ROR? agonists may hold utility in treatment of autism and that optimized ROR? inverse agonists may hold utility in the treatment of depression. In order to address these hypotheses we propose the following 2 specific aims:
Aim 1 : Develop and optimize ROR? agonists for treatment of autism and Aim 2: Develop and optimize ROR? inverse agonists for treatment of depression. The studies described in this application are highly innovative given that we have developed a range of novel, first-in-class ROR ligands and we have demonstrated that these compounds have efficacy in mouse models of autism as well as TH17 cell mediated diseases. If successful, this work would have significant impact given the potential translation of this work into drugs in the clinic.

Public Health Relevance

We have developed several synthetic ligands that target the ROR class of orphan nuclear receptors. Preliminary data suggests that ROR? agonists may hold utility in the treatment of autism while ROR? inverse agonists may hold utility in the treatment of depression. Here, we focus on development and optimization of ROR? agonists and ROR? inverse agonists and assess their activity in models of autism and depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Drug Discovery for the Nervous System Study Section (DDNS)
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Michelotti, Enrique
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St. Louis College of Pharmacy
Schools of Pharmacy
Saint Louis
United States
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Billon, Cyrielle; Sitaula, Sadichha; Burris, Thomas P (2017) Metabolic Characterization of a Novel ROR? Knockout Mouse Model without Ataxia. Front Endocrinol (Lausanne) 8:141
Wang, Yongjun; Billon, Cyrielle; Walker, John K et al. (2016) Therapeutic Effect of a Synthetic ROR?/? Agonist in an Animal Model of Autism. ACS Chem Neurosci 7:143-8
Billon, Cyrielle; Sitaula, Sadichha; Burris, Thomas P (2016) Inhibition of ROR?/? suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation. Mol Metab 5:997-1005
Girardet, Clemence; Burris, Thomas P; Butler, Andrew A (2015) SIRT1 in the Ventromedial Hypothalamus: A Nutrient Sensor Input Into the Internal Timekeeper. Endocrinology 156:1936-8
Solt, Laura A; Burris, Thomas P (2015) Th17 cells in Type 1 diabetes: a future perspective. Diabetes Manag (Lond) 5:247-250
Solt, Laura A; Banerjee, Subhashis; Campbell, Sean et al. (2015) ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes. Endocrinology 156:869-81
Banerjee, Subhashis; Wang, Yongjun; Solt, Laura A et al. (2014) Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat Commun 5:5759
Kojetin, Douglas J; Burris, Thomas P (2014) REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 13:197-216
Vieira, Elaine; Burris, Thomas P; Quesada, Ivan (2014) Clock genes, pancreatic function, and diabetes. Trends Mol Med 20:685-93
Griffett, Kristine; Burris, Thomas P (2013) The mammalian clock and chronopharmacology. Bioorg Med Chem Lett 23:1929-34

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