Integrating differential gene expression analysis with perturbagen-response signatures may identify novel therapies for thyroid-associated orbitopathy

John Y. Lee, Ryan A. Gallo, Paul J. Ledon, Wensi Tao, David T. Tse, Daniel Pelaez, Sara T. Wester

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify small molecules that revert pathologic gene signature and alter disease phenotype in orbital adipose stem cells (OASCs) derived from patients with thyroid-associated orbitopathy (TAO). Methods: Differentially expressed genes identified via RNA sequencing were inputted into LINCS L1000 Characteristic Direction Signature Search Engine (L1000CDS2 )to predict candidate small molecules to reverse pathologic gene expression. TAO OASC cell lines were treated in vitro with six identified small molecules (Torin-2, PX12, withaferin A, isoliquiritigenin, mitoxantrone, and MLN8054), and expression of key adipogenic and differentially expressed genes was measured with quantitative polymerase chain reaction after 7 days of treatment. OASCs were differentiated into adipocytes, treated for 15 days, and stained with Oil Red O (OD 490 nm) to evaluate adipogenic changes. Results: The expression of key differentially expressed genes (IRX1, HOXB2, S100B, and KCNA4) and adipogenic genes (peroxisome proliferator activated receptor-γ, FABP4) was significantly decreased in TAO OASCs after treatment (P < .05). In treated TAO adipocytes (n = 3), all six tested small molecules yielded significant decrease (P < .05) in Oil Red O staining. In treated non-TAO adipocytes (n = 3), only three of the drugs yielded a significant decrease in Oil Red O staining. Conclusions: Combining disease expression signatures with LINCS small molecule prediction software can identify promising preclinical drug candidates for TAO. Translational Relevance: These findings may offer insight into future potential therapeutic options for TAO and demonstrate a streamlined model to predict drug candidates for other diseases.

Original languageEnglish (US)
Article number39
Pages (from-to)1-12
Number of pages12
JournalTranslational Vision Science and Technology
Volume9
Issue number9
DOIs
StatePublished - 2020

Keywords

  • Adipogenesis
  • Graves’ ophthalmopathy
  • LINCS
  • Orbital adipose stem cells
  • Thyroid eye disease
  • Thyroid-associated orbitopathy

ASJC Scopus subject areas

  • Biomedical Engineering
  • Ophthalmology

Fingerprint Dive into the research topics of 'Integrating differential gene expression analysis with perturbagen-response signatures may identify novel therapies for thyroid-associated orbitopathy'. Together they form a unique fingerprint.

  • Cite this