Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We use high throughput screening (HTS) and chemical modification to develop small molecule ligands (SMLs) for TSH receptors (TSH-R) and TRH receptors (TRH-R). During this year, we continued our development of these SMLs. 1) In preliminary studies, it was shown that TRH itself when administered intravenously to patients with cancer-related fatigue alleviated some of their fatigue symptoms. However, TRH is not a good drug as it is rapidly degraded in the circulation and does not cross the blood brain barrier efficiently. We were intrigued by this observation and with a goal to eventually develop new TRH-R agonists, we decided to develop a mouse model of fatigue to test the activities of new compounds on fatigue. We began by developing a sensitive treadmill test for fatigue-like behavior and showed that it quantitatively measured fatigue-like behavior in mice. We have now used this test to show that a TRH analog, taltirelin, alleviates fatigue-like behavior in mouse models of fatigue induced by cancer burden, chemotherapeutic agents and radiation. Of note, taltirelin was effective when given orally. (Taltirelin has been used to treat a neurologic disorder in Japanese patients for more than fifteen years.) Based on these findings we obtained approval to test taltirelin in patients as an Investigational New Drug agreement from the USA Food and Drug Administration. 2) Based on our previous findings that TSH-Rs on pre-osteoblastic cells could induce their differentiation to osteoblasts via a beta-arrestin-mediated signaling pathway, we performed a HTS to discover an agonist that was biased toward beta-arrestin signaling (and not toward G protein signaling). This is important because activation of the beta-arrestin pathway leads to bone formation whereas activation of G protein signaling leads to bone loss. We were successful and generated the first TSH-R beta-arrestin-biased agonist that we will use to study pre-osteoblast differentiation and that may be a lead for drug development to treat osteoporosis in humans.
| Morgan, Sarah J; Neumann, Susanne; Gershengorn, Marvin C (2018) Normal Human Thyrocytes in Culture. Methods Mol Biol 1817:1-7 |
| Dougherty, John P; Wolff, Brian S; Cullen, Mary J et al. (2017) Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. Pharmacol Res 124:1-8 |
| Neumann, Susanne; Padia, Umesh; Cullen, Mary Jane et al. (2016) An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties. Front Endocrinol (Lausanne) 7:105 |
| Dougherty, John P; Springer, Danielle A; Gershengorn, Marvin C (2016) The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse. J Vis Exp : |
| Krieger, Christine C; Place, Robert F; Bevilacqua, Carmine et al. (2016) TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis. J Clin Endocrinol Metab 101:2340-7 |
| Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C (2016) Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. Endocrinology 157:2173-81 |
| Krieger, Christine C; Neumann, Susanne; Place, Robert F et al. (2015) Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves' disease immunoglobins. J Clin Endocrinol Metab 100:1071-7 |
| Boutin, Alisa; Eliseeva, Elena; Gershengorn, Marvin C et al. (2014) ?-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J 28:3446-55 |
| Turcu, Adina F; Kumar, Seema; Neumann, Susanne et al. (2013) A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 98:2153-9 |
| Geras-Raaka, Elizabeth; Neumann, Susanne; Gershengorn, Marvin C (2013) Persistent cAMP Signaling by TSH Receptors Revealed by Phosphodiesterase Inhibition. Thyroid : |
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