Department of Immunology and Microbiology
Department of Molecular Medicine
Faculty, Graduate Program
Nuclear receptors (NR) 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 NRs roles in vivo in the context of various diseases. Ultimately, we aim to identify and develop small molecule modulators of NRs for the therapeutic treatment of autoimmune and metabolic disorders.
NRs in Autoimmunity
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 more recently identified lineage of CD4+ T helper cells that 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. Since NRs, including RORa and RORg, 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. Other interests in the lab include understanding NRs roles in immune populations outside of TH17 cells.
NRs and Metabolic Diseases
Metabolism is the processes by which an organism obtains and makes energy from nutrient sources. Maintaining metabolic homeostasis is crucial for optimal health and dysregulation of various metabolic pathways can lead to disease states, including Type 2 diabetes and obesity. Through transcriptional control of gene networks, NRs have been demonstrated to play central roles in regulating metabolism in a tissue-specific manner. Altered signaling by NRs may cause an imbalance in metabolic homeostasis and contribute to pathogenesis of metabolic diseases. Therefore, selective targeting of various NRs may be an attractive strategy for the treatment of metabolic diseases.
B.A., Psychology, Boston College
Ph.D., Immunology, University of Pennsylvania
Postdoctoral fellow (2009-2013), The Scripps Research Institute, Jupiter, FL
Ruth L. Kirschstein National Research Service Awards, NIH (2010-2013)
Sun Y, Liu CH, SanGiovanni JP, Evans LP, Tian KT, Zhang B, Stahl A, Pu WT, Kamenecka TM, Solt LA, Chen J. Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10401-6.
Flaveny CA, Griffett K, El-Gendy Bel-D, Kazantzis M, Sengupta M, Amelio AL, Chatterjee A, Walker J, Solt LA, Kamenecka TM, Burris TP. Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis. Cancer Cell. 2015 Jul 13;28(1):42-56.
Sitaula S, Billon C, Kamenecka TM, Solt LA, Burris TP. Suppression of atherosclerosis by synthetic REV-ERB agonist. Biochem Biophys Res Commun. 2015 May 8;460(3):566-71.
Solt LA, Banerjee S, Campbell S, Kamenecka TM, Burris TP. ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes. Endocrinology. 2015 Mar;156(3):869-81.
Banerjee S, Wang Y, Solt LA, Griffett K, Kazantzis M, Amador A, El-Gendy BM, Huitron-Resendiz S, Roberts AJ, Shin Y, Kamenecka TM, Burris TP. Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat Commun. 2014 Dec 23;5:5759.
Matta-Camacho E, Banerjee S, Hughes TS, Solt LA, Wang Y, Burris TP, Kojetin DJ. Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist. J Biol Chem. 2014 Jul 18;289(29):20054-66.
Woldt E, Sebti Y, Solt LA, Duhem C, Lancel S, Eeckhoute J, Hesselink MK, Paquet C, Delhaye S, Shin Y, Kamenecka TM, Schaart G, Lefebvre P, Nevière R, Burris TP, Schrauwen P, Staels B, Duez H. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med. 2013 Aug;19(8):1039-46.
Griffett K, Solt LA, El-Gendy Bel-D, Kamenecka TM, Burris TP. A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67.
Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev. 2013 Mar 1;65(2):710-78.
Kumar N, Lyda B, Chang MR, Lauer JL, Solt LA, Burris TP, Kamenecka TM and Griffin PR. Identification of SR2211: A Potent Synthetic RORγ-Selective Modulator. ACS Chem Biol. 2012 Apr 20;7(4):672-7.
Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo SH, Takahashi JS, Butler AA, Kamenecka TM and Burris TP. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012; Mar 29; 485 (7396): 62-8.
Doerdelmann T, Kojetin DJ, Baird-Titus JM, Solt LA, Burris TP, Rance M. Structural and biophysical insights into the ligand-free Pitx2 homeodomain and a ring dermoid of the cornea inducing homeodomain mutant. Biochemistry. 2012 Jan 17;51(2):665-76.
Wang Y, Solt LA, Kojetin DJ, Burris TP. Regulation of p53 stability and apoptosis by a ROR agonist. PLoS One. 2012;7(4):e34921.
Solt LA, Kamenecka TM and Burris TP. LXR-Mediated Inhibition of CD4+ T Helper Cells. PLoS One. 2012; 7(9):e46615.
Solt LA, Kumar N, He Y, Kamenecka TM, Griffin PR and Burris TP. Identification of a Selective RORγ Ligand that Suppresses TH17 cells and Stimulates T Regulatory Cells. ACS Chem Biol. 2012; 7(9): 1515-9.
Solt LA and Burris TP. Action of RORs and Their Ligands in (patho) Physiology. Trends Endocrinol Metab. 2012; 23(12): 619-27.
Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidović D, Schürer SC, Xu J, Wagoner G, Drew PD, Griffin PR and Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011 Apr 28; 472 (7344): 491-4.
Solt LA, Kojetin DJ and Burris TP. The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med Chem. 2011 Apr; 3 (5): 623-38.
Kumar N, Kojetin DJ, Solt LA, Kumar KG, Nuhant P, Duckett DR, Cameron MD, Butler AA, Roush WR, Griffin PR and Burris TP. Identification of SR3335 (ML-176): A Synthetic RORα Selective Inverse Agonist. ACS Chem Biol. 2011 Mar 18; 6 (3): 218-22.
Begriche K1, Levasseur PR, Zhang J, Rossi J, Skorupa D, Solt LA, Young B, Burris TP, Marks DL, Mynatt RL, Butler AA. Genetic dissection of the functions of the melanocortin-3 receptor, a seven-transmembrane G-protein-coupled receptor, suggests roles for central and peripheral receptors in energy homeostasis. J Biol Chem. 2011;286(47):40771-81.
Kumar N, Solt LA, Wang Y, Rogers PM, Bhattacharyya G, Kamenecka TM, Stayrook KR, Crumbley C, Floyd ZE, Gimble JM, Griffin PR and Burris TP. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology. 2010 July;151(7):3015-25.
Wang YJ, Solt LA and Burris TP. Regulation of FGF21 Expression and Secretion by Retinoic Acid Receptor-Related Orphan Receptor alpha. J. Biol. Chem. 2010. May 21: 285 (21): 15668-73.
Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Busby SA, Garcia-Ordonez R, Burris TP and Griffin PR. The benzenesulfoamide T0901317 is a novel RORα/γ Inverse Agonist. Mol. Pharm. 2010. 77(2): 228-36.
Wang Y, Kumar N, Solt LA, Richardson TI, Helvering LM, Crumbley C, Garcia-Ordonez RA, Stayrook KR, Zhang X, Novick S, Chalmers MJ, Griffin PR and Burris TP. Modulation of RORα and RORγ activity by 7-oxygenated sterol ligands. J. Bio.Chem. 2010. 285 (7): 5013-25.
Solt LA, Griffin PR and Burris TP. Ligand Regulation of Retinoic Acid Receptor-Related Orphan Receptors (RORs): Implications for Development of Novel Therapeutics. Curr. Opin. Lipidol. 2010. 21 (3): 204-11.