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Journal of Pharmacology and Experimental Therapeutics

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OtherDrug Discovery and Translational Medicine

Utilizing DREADD chemogenetic tools to identify beneficial GPCR signaling for fibrosis

Ji Zhang, Eyal Vardy, Eric Muise, Tzu-Ming Wang, Richard Visconti, Ashita Vadlamudi, Shirly Pinto and Andrea M. Peier
Journal of Pharmacology and Experimental Therapeutics August 26, 2020, JPET-AR-2020-000103; DOI: https://doi.org/10.1124/jpet.120.000103
Ji Zhang
1Merck & Co., Inc., United States
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  • For correspondence: ji.zhang1@merck.com
Eyal Vardy
2Merck & Co., Inc.; Kallyope, Inc., United States
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Eric Muise
3merck, United States of America
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Tzu-Ming Wang
1Merck & Co., Inc., United States
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Richard Visconti
1Merck & Co., Inc., United States
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Ashita Vadlamudi
1Merck & Co., Inc., United States
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Shirly Pinto
2Merck & Co., Inc.; Kallyope, Inc., United States
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Andrea M. Peier
1Merck & Co., Inc., United States
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Abstract

Fibrosis or accumulation of extracellular matrix is an evolutionarily conserved mechanism adopted by an organism as a response to chronic injury. Excessive fibrosis, however, leads to disruption of organ homeostasis and is a common feature of many chronic diseases. G protein-coupled receptors (GPCRs) are important cell signaling mediators and represent molecular targets for many FDA approved drugs. To identify new targets for fibrosis, we utilized a synthetic GPCR system named Designed Receptors Exclusively Activated by Designer Drugs (DREADDs) to probe signaling pathways essential for fibrotic response. We found that upon expression in human lung fibroblasts, activation of Gq and Gs-DREADDs abrogated the induction of TGFβ-induced fibrosis marker genes. Genome-wide transcriptome analysis identified dysregulation of multiple GPCRs in lung fibroblasts treated with TGFβ. To investigate endogenous GPCR modulating TGFβ signaling, we selected 13 GPCRs that signal through Gq or Gs and activated them by using specific agonists. We examined the impact of each agonist and how activation of endogenous GPCR affects TGFβ signaling. Among which, prostaglandin receptor agonists demonstrated the strongest inhibitory effect on fibrosis. Together, we have demonstrated that DREADDs system is a valuable tool to identify beneficial GPCR signaling for fibrosis. This study in fibroblasts has served as a proof-of-concept and allowed us to further develop in vivo models for fibrosis GPCR discovery.

Significance Statement Fibrosis is the hallmark of many end-stage cardiometabolic diseases and there is an unmet medical need to discover new anti-fibrotic therapies, reduce disease progression, and bring clinically meaningful efficacy to patients. Our work utilizes DREADD chemogenetic tools to identify beneficial GPCR signaling for fibrosis, providing new insights into GPCR drug discovery.

  • fibroblasts
  • g protein-coupled receptors (GPCRS)
  • G proteins
  • transforming growth factor (TGF)
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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OtherDrug Discovery and Translational Medicine

GPCR signaling in Fibrosis

Ji Zhang, Eyal Vardy, Eric Muise, Tzu-Ming Wang, Richard Visconti, Ashita Vadlamudi, Shirly Pinto and Andrea M. Peier
Journal of Pharmacology and Experimental Therapeutics August 26, 2020, JPET-AR-2020-000103; DOI: https://doi.org/10.1124/jpet.120.000103

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OtherDrug Discovery and Translational Medicine

GPCR signaling in Fibrosis

Ji Zhang, Eyal Vardy, Eric Muise, Tzu-Ming Wang, Richard Visconti, Ashita Vadlamudi, Shirly Pinto and Andrea M. Peier
Journal of Pharmacology and Experimental Therapeutics August 26, 2020, JPET-AR-2020-000103; DOI: https://doi.org/10.1124/jpet.120.000103
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